Methods of identifying agents inhibiting fatty acid transport proteins

ABSTRACT

A family of fatty acid transport proteins (FATPS) mediate transport of long chain fatty acids (LCFAs) across cell membranes into cells. These proteins exhibit different expression patterns among the organs of mammals. Nucleic acids encoding FATPs of this family, vectors comprising these nucleic acids, as well as the production of FATP proteins in host cells are described. Also described are methods to test FATPs for fatty acid transport function, and methods to identify inhibitors or enhancers of transport function. The altering of LCFA uptake by administering to the mammal an inhibitor or enhancer of FATP transport function of a FATP in the small intestine can decrease or increase calories available as fats, and can decrease or increase circulating fatty acids. The organ specificity of FATP distribution can be exploited in methods to direct drugs, diagnostic indicators and so forth to an organ such as the heart.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/071,374 entitled “Identification of a Family of Fatty AcidTransporters Conserved From Mycobacterium to Man,” by Andreas Stahl,David Hirsch and Harvey F. Lodish, filed on Jan. 15, 1998; U.S.Provisional Application No. 60/093,491 entitled “Fatty Acid TransportProteins,” by Andreas Stahl, David J. Hirsch, Harvey F. Lodish, Ruth E.Gimeno and Louis A. Tartaglia, filed on Jul. 20, 1998; and U.S.Provisional Application No. 60/110,941 entitled “Fatty Acid TransportProteins,” by Andreas Stahl, David J. Hirsch, Harvey F. Lodish, Ruth E.Gimeno and Louis A. Tartaglia, filed on Dec. 4, 1998. The teachings ofeach of these referenced applications are incorporated herein byreference in their entirety.

GOVERNMENT SUPPORT

The invention was supported, in whole or in part, by National Institutesof Health Grant DK 47618 and National Institutes of Health Grant 5 T32CA 09541. The United States Government has certain rights in theinvention.

BACKGROUND OF THE INVENTION

Long chain fatty acids (LCFAs) are an important source of energy formost organisms. They also function as blood hormones, regulating keymetabolic functions such as hepatic glucose production. Although LCFAscan diffuse through the hydrophobic core of the plasma membrane intocells, this nonspecific transport cannot account for the high affinityand specific transport of LCFAs exhibited by cells such as cardiacmuscle, hepatocytes, enterocytes, and adipocytes. The molecularmechanisms of LCFA transport remains largely unknown. Identifying thesemechanisms can lead to pharmaceuticals that modulate fatty acid uptakeby the intestine and by other organs, thereby alleviating certainmedical conditions (e.g. obesity).

SUMMARY OF THE INVENTION

Described herein is a diverse family of fatty acid transport proteins(FATPs) which are evolutionarily conserved; these FATPs are plasmamembrane proteins which mediate transport of LCFAs across the membranesand into cells. Members of the FATP family described herein are presentin a wide variety of organisms, from mycobacteria to humans, and exhibitvery different expression patterns in tissues among the organisms. FATPfamily members are expressed in prokaryotic and eukaryotic organisms andcomprise characteristic amino acid domains or sequences which are highlyconserved across family members. In addition, the function of the FATPgene family is conserved throughout evolution, as shown by the fact thatthe Caenorhabditis (C). elegans and mycobacterial FATPs described hereinfacilitate LCFA uptake when they are overexpressed in COS cells orEscherichia (E.) coli, respectively. FATPs are expressed in a widevariety of tissues, including all tissues which are important to fattyacid metabolism (uptake and processing).

In specific embodiments, FATPs of the present invention are from suchdiverse organisms as humans (Homo (H.) sapiens), mice, (Mus (M.)musculus), F. rubripes, C. elegans, Drosophila (D.) melanogaster,Saccharomyces (S.) cerevisiae, Aspergillus nidulans, Cochlioboluheterostrophus, Magnaporthe grisea and Mycobacterium (M.), such as M.tuberculosis. As described herein, four novel mouse FATPs, referred toas mmFATP2, mmFATP3, mmFATP4 and mmFATP5, and six human FATPs, referredto as hsFATP1, hsFATP2, hsFATP3, hsFATP4, hsFATP5 and hsFATP6, have beenidentified. All four novel murine FATPs (mmFATP2-5) and a previouslyidentified murine FATP (renamed herein FATP1) have orthologs in humans(hsFATP1-5); the sixth human FATP (hsFATP6) does not as yet have a mouseortholog. The expression patterns of these FATPs vary, as described indetail below.

The present invention relates to FATP family members from prokaryotesand eukaryotes, nucleic acids (DNA, RNA) encoding FATPs, and nucleicacids which are useful as probes or primers (e.g., for use inhybridization methods, amplification methods) for example, in methods ofdetecting FATP-encoding genes, producing FATPs, and purifying orisolating FATP-encoding DNA or RNA. Also the subject of this inventionare antibodies (polyclonal or monoclonal) which bind an FATP or FATPs;methods of identifying additional FATP family members (for example,orthologs of those FATPs described herein by amino acid sequence) andvariant alleles of known FATP genes; methods of identifying compoundswhich bind to an FATP, or modulate or alter (enhance or inhibit) FATPfunction; compounds which modulate or alter FATP function; methods ofmodulating or altering (enhancing or inhibiting) FATP function and,thus, LCFA uptake into tissues of a mammal (e.g. human) by administeringa compound or molecule (a drug or agent) which increases or reduces FATPactivity; and methods of targeting compounds to tissues by administeringa complex of the compound to be targeted to tissues and a componentwhich is bound by an FATP present on cells of the tissues to which thecompound is to be targeted. For example, a complex of a drug to bedelivered to the liver and a component which is bound by an FATP presenton liver cells (e.g., FATP5) can be administered.

In one embodiment, the present invention relates to modulating oraltering (enhancing or inhibiting/reducing) LCFA uptake in the smallintestine and, thus, increasing or reducing the number of calories inthe form of fats available to an individual. In another embodiment, thepresent invention relates to inhibiting or reducing LCFA uptake in thesmall intestine in order to reduce circulating fatty acid levels; thatis, LCFA uptake in the small intestine is reduced and, therefore,circulating (blood) levels are not as high as they otherwise would be.FATP4 has been shown to be expressed in epithelial cells of the smallintestine and particularly in the brush border layer of the smallintestine. FATP2 has also been shown to be expressed at low levels inepithelial cells of the small intestine, particularly in the duodenum.In contrast, FATP1, FATP3, FATP5 and FATP6 were not detected in any ofthe intestinal tissues. Thus, also described herein are FATPs which arepresent in the epithelial cell layer of the small intestine where theymediate LCFA uptake. These FATPs, particularly FATP4 and also FATP2, aretargets for methods and drugs which block their function or activity andare useful in treating obesity, diabetes and heart disease. The abilityof these FATPs to mediate fat uptake can be modulated or altered(enhanced or inhibited), thus modulating fat uptake in the smallintestine. This can be done, for example, by administering to anindividual, such as a human or other animal, a drug which blocksinteraction of LCFAs with FATP4 and/or FATP2 in the small intestine,thus inhibiting LCFA passage into the cells of the small intestine. As aresult, fat absorption is reduced and, although the individual hasconsumed a certain quantity of fat, the LCFAs are not absorbed to thesame extent they would have been in the absence of the compoundadministered.

Thus, one embodiment of this invention is a method of reducing LCFAuptake (absorption) in the small intestine and, as a result, reducingcaloric uptake in the form of fat. A further embodiment is a compound(drug) useful in inhibiting or reducing fat absorption in the smallintestine. In another embodiment, the invention is a method of reducingcirculating fatty acid levels by administering to an individual acompound which blocks interactions of LCFAs with FATP4 and/or FATP2 inthe small intestine, thus inhibiting LCFA passage into cells of thesmall intestine. As a result, fatty acids pass into the circulatorysystem at a diminished level and/or rate, and circulating fatty acidlevels are lower than they would be in the absence of the compoundadministered. This method is particularly useful for therapy inindividuals who are at risk for or have hyperlipidemia. That is, it canbe used to prevent the occurrence of elevated levels of lipids in theblood or to treat an individual in whom blood lipid levels are elevated.Also the subject of this invention is a method of identifying compoundswhich alter FATP function (and thus, in the case of FATP2 and/or FATP4,alter LCFA uptake in the small intestine).

In another embodiment, the present invention relates to a method ofmodulating or altering (enhancing or inhibiting) the function of FATP6,which is expressed at high levels in the heart. A method of inhibitingFATP6 function is useful, for example, in individuals with heartdisease, such as ischemia, since reducing LCFA uptake into heart musclein an individual who has ischemic heart disease, which may be manifestedby, for example, angina or heart attack, can reduce symptoms or reducethe extent of damage caused by the ischemia. In this embodiment, a drugwhich inhibits FATP6 function is administered to an individual who hashad or is having a heart attack, to reduce LCFA uptake by theindividual's heart and, as a result, reduce the damage caused byischemia. In a further embodiment, this invention is a method oftargeting a compound, such as a therapeutic drug or an imaging reagent,to heart tissue by administering to an individual (e.g., a human) acomplex of the compound and a component (e.g., a LCFA or LCFA-likecompound) which is bound by an FATP (e.g., FATP6) present in cells ofheart tissue.

In a further embodiment, LCFA uptake by the liver is modulated oraltered (enhanced or reduced), in an individual. For example, a drugwhich inhibits the function of an FATP present in liver (e.g., FATP5) isadministered to an individual who is diabetic, in order to reduce LCFAuptake by liver cells and, thus reduce insulin resistance.

The present invention, thus, provides methods which are useful to alter,particularly reduce, LCFA uptake in individuals and, as a result, toalter (particularly reduce), availability of the LCFAs for furthermetabolism. In a specific embodiment, the present invention providesmethods useful to reduce LCFA uptake and, thus, fatty acid metabolism inindividuals, with the result that caloric availability from fats isreduced, and circulating fatty acid levels are lower than they otherwisewould be. These methods are useful, for example, as a means of weightcontrol in individuals, (e.g., humans) and as a means of preventingelevated serum lipid levels or reducing serum lipid levels in humans.FATPs expressed in the small intestine, such as FATP4, are usefultargets to be blocked in treating obesity (e.g., chronic obesity) or tobe enhanced in treating conditions in which enhanced LCFA uptake isdesired (e.g., malabsorption syndrome or other wasting conditions).

The identification of this evolutionarily conserved fatty acidtransporter family will allow a better understanding of the mechanismswhereby LCFAs traverse the lipid bilayer as well as yield insight intothe control of energy homeostasis and its dysregulation in diseases suchas diabetes and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the amino acid sequence alignment of FATPs: mmFATP1 (SEQ IDNO:92), mmFATP2 (SEQ ID NO:93), mmFATP3 (SEQ ID NO:94), mmFATP4 (SEQ IDNO:95), mmFATP5 (SEQ ID NO:96), ceFATPa (SEQ ID NO:97), scFATP (SEQ IDNO:98) and mtFATP (SEQ ID NO:99). The underlining (amino acid residues204-212 of mtFATP) indicates an AMP binding motif which is found in manyclasses of proteins; the underlining at amino acid residues 204-507 ofthe mtFATP sequence indicates the FATP 360 amino acid signaturesequence.

FIGS. 2A-2D show results of LCFA uptake assays. FIGS. 2A-2D: COS cellswere cotransfected using the DEAE-dextran method with the mammalianexpression vectors pCDNA-CD2 either alone (control; FIG. 2A) or incombination with one of the FATP-containing expression vectors(pCDNA-mmFATP1, FIG. 2B; pCDNA-mmFATP2, FIG. 2C; or pCMV-SPORT2-mmFATP5,FIG. 2D) as described in Materials and Methods for Example 2. COS cellswere gated on forward scatter (FSC) and side scatter (SS), and theresults shown represent >10,000 cells. Cells exhibiting >300 CD2fluorescence units (vertical line) representing 15% of all cells weredeemed CD2 positive.

FIG. 3 is a graph of fluorescence of cells expressing a FATP gene. As inFIGS. 2A-2D, COS cells were cotransfected with pCDNA-CD2 either alone(control) or in combination with one of the FATP-containing expressionvectors (pCDNA-mmFATP1, pCDNA-mmFATP2, pCMV-SPORT2-mmFATP5, orpCDNA-ceFATPb). The mean BODIPY-FA fluorescence of the CD2-positivecells is plotted; results shown represent the average of threeexperiments, each consisting of greater than 50,000 COS cells. Note thata logarithmic scale is used on the ordinate.

FIG. 4 is a graph of the uptake of palmitate with time. The full-lengthcoding region of mtFATP (squares) or a control protein (TFE3; circles)was subdloned into the inducible, prokaryotic expression vector pET(Novagen). Expression from the resulting plasmid was induced (solidsymbols) in transformed E. coli cells with 1 mMisopropyl-β-D-thiogalactoside (IPTG) for 1 hour, or cells were leftuninduced (open symbols). Data points were done in triplicate and countswere normalized to the number of bacteria as determined by OD₆₀₀.

FIG. 5 is a phylogenetic tree produced by aligning complete and partialsequences for FATP genes from human, rat, mouse, puffer fish, D.melanogaster, C. elegans, S. cerevisiae, and M. tuberculosis usingClustalX and using these data to produce a phylogenetic tree usingTreeViewPPC. The bar indicates the number of substitutions per residue,i.e., 0.1 corresponds to a distance of 10 substitutions per 100residues.

FIG. 6 shows a comparison of the FATP signature sequences of mmFATP I(SEQ ID NO:1), mmFATP5, (SEQ ID NO:2), ceFATPa (SEQ ID NO:3), scFATP(SEQ ID NO:4) and mtFATP (SEQ ID NO:5).

FIG. 7 shows the sequence identity among the FATP family members andVLACs, based on the 360 amino acid signature sequence of FATP from FIG.1.

FIGS. 8A and 8B are the mmFATP3 DNA sequence (SEQ ID NO:6).

FIG. 9 is the mmFATP3 protein sequence (SEQ ID NO:7).

FIGS. 10A and 10B are the mmFATP4 DNA sequence (SEQ ID NO:8).

FIG. 11 is the mmFATP4 protein sequence (SEQ ID NO:9).

FIGS. 12A and 12B are the mmFATP5 DNA sequence (SEQ ID NO:10).

FIG. 13 is the mmFATP5 protein sequence (SEQ ID NO:11).

FIGS. 14A and 14B are the hsFATP2 DNA sequence (SEQ ID NO:12).

FIG. 15 is the hsFATP2 protein sequence (SEQ ID NO:13).

FIGS. 16A and 16B are the hsFATP3 DNA sequence (SEQ ID NO:14).

FIG. 17 is the hsFATP3 protein sequence (SEQ ID NO:15).

FIGS. 18A and 18B are the hsFATP4 DNA sequence (SEQ ID NO:16).

FIG. 19 is the hsFATP4 protein sequence (SEQ ID NO:17).

FIGS. 20A and 20B are the hsFATP5 DNA sequence (SEQ ID NO:18).

FIG. 21 is the hsFATP5 protein sequence (SEQ ID NO:19).

FIGS. 22A and 22B are the hsFATP6 DNA sequence (SEQ ID NO:20).

FIG. 23 is the hsFATP6 protein sequence (SEQ ID NO:21).

FIGS. 24A and 24B are the mtFATP DNA sequence (SEQ ID NO:22).

FIG. 25 is the mtFATP protein sequence (SEQ ID NO:23).

FIG. 26 shows the DNA sequence (SEQ ID NO:24) and predicted amino acidsequence (SEQ ID NO:25) of human FATP1.

FIG. 27 shows the DNA sequence (SEQ ID NO:26) and predicted amino acidsequence (SEQ ID NO:27) of human FATP4.

FIG. 28A is a hydrophobicity plot for hsFATP1, showing that it hasmultiple membrane-spanning domains.

FIG. 28B is the amino acid composition of hsFATP1.

FIG. 28C is a hydrophilicity plot for hsFATP1, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

FIG. 29A is a hydrophobicity plot for hsFATP4, showing that it hasmultiple membrane-spanning domains.

FIG. 29B is a listing of the amino acid composition of hsFATP4.

FIG. 29C is a hydrophilicity plot for hsFATP4, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

FIGS. 30A and 30B show a comparison of the nucleotide sequence of humanFATP1 (SEQ ID NO:28) and the nucleotide sequence of mouse FATP1 (SEQ IDNO:29).

FIGS. 31A and 31B show a comparison of the nucleotide sequence of humanFATP4 (SEQ ID NO:30) and the nucleotide sequence of mouse FATP4 (SEQ IDNO:31).

FIG. 32 shows a comparison of the amino acid sequence of human FATP1(SEQ ID NO:32) and the amino acid sequence of mouse FATP1 (SEQ IDNO:33). Shaded amino acid residues match the concensus sequence exactly

FIG. 33 shows a comparison at the amino acid level of human FATP4 (SEQID NO:34) and mouse FATP4 (SEQ ID NO:35). Shaded amino acid residuesmatch the concensus sequence exactly.

FIG. 34 shows the nucleotide sequence (SEQ ID NO:36) and predicted aminoacid sequence (SEQ ID NO:37) of hsFATP6.

FIG. 35A is a hydrophobicity plot for hsFATP6, showing that it hasmultiple membrane-spanning domains.

FIG. 35B is a listing of the amino acid composition of hsFATP6.

FIG. 35C is a hydrophilicity plot for hsFATP6, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

FIG. 36 shows an alignment of the amino acid sequences of hsFATP1 (SEQID NO:38), hsFATP4 (SEQ ID NO:39) and hsFATP6 (SEQ ID NO:40). Shadedamino acid residues match the consensus sequence exactly.

FIG. 37 shows results of assessment of fatty acid uptake by human FATP1and human FATP4. The percent of CD2-positive cells exhibiting aBODIPY-fluorescence of more than 300 arbitrary units is plotted for thethree different conditions tested.

FIG. 38 is a graph showing uptake of tritiated oleate, with time, by 293cells transfected with either (diamonds) a plasmid for expression ofhuman FATP4 or (squares) a control plasmid.

FIG. 39 is an illustration of the amino acid sequences of human FATP4(SEQ ID NO:41) and mouse FATP4 (SEQ ID NO:42) compared to human FATP1(SEQ ID NO:43). Shown by underlining are the FATP consensus sequence(236-556 of hsFATP1) and the AMP-binding motif (246-254 of hsFATP1). Thehuman FATPs were cloned by screening libraries with sequences from ESTs(expressed sequence tags). Mouse FATP4 was cloned by PCR usingdegenerate primers.

FIG. 40 is a graph showing the uptake, with time, of tritiated oleate bymouse enterocytes in the presence of no oligonucleotide (squares), senseoligonucleotide (circles) or antisense oligonucleotide (diamonds).

FIG. 41 is a bar graph showing uptake of tritiated oleate, by mouseenterocytes in the presence of various concentrations of antisense(solid bars), mismatch (stippled bars) or sense (lined bars)oligonucleotides.

FIG. 42 is a bar graph showing uptake of tritiated oleate and uptake of³⁵S-labeled methionine by mouse enterocytes to which were added nooligonucleotide, the antisense oligonucleotide, or the mismatcholigonucleotide.

FIG. 43A is the nucleotide sequence of the gene encoding mouse FATP4(SEQ ID NO:44).

FIG. 43B is the amino acid sequence of mouse FATP4 protein (SEQ IDNO:45).

FIGS. 44A, 44B, and 44C are the hsFATP1 DNA sequence (SEQ ID NO:46).Coding region: 175-2115 (1941 nt).

FIG. 45 is the hsFATP1 protein sequence (SEQ ID NO:47).

FIGS. 46A and 46B are the hsFATP2 DNA sequence (SEQ ID NO:48). Codingregion: 223-2085 (1863 nt).

FIG. 47 is the hsFATP2 protein sequence (SEQ ID NO:49).

FIG. 48 is the partial DNA sequence of hsFATP3 (SEQ ID NO:50). Codingregion: 1-993.

FIG. 49 is the partial protein sequence of hsFATP3 (SEQ ID NO:51).

FIGS. 50A, 50B, and 50C are the hsFATP4 DNA sequence (SEQ ID NO:52).Coding region: 208-2139 (1932 nt).

FIG. 51 is the hsFATP4 protein sequence (SEQ ID NO:53).

FIG. 52 is the hsFATP5 partial DNA sequence (SEQ ID NO:54). Codingregion: 1-1062.

FIG. 53 is the hsFATP5 partial protein sequence (SEQ ID NO:55).

FIGS. 54A, 54B, and 54C are the hsFATP6 DNA sequence (SEQ ID NO:56).Coding region: 643-2502 (1860 nt).

FIG. 55 is the hsFATP6 protein sequence (SEQ ID NO:57).

FIGS. 56A, 56B, and 56C are the rnFATP1 DNA sequence (m=Rattusnorvegicus; (SEQ ID NO:58). Coding region: 75-2015 (1941 nt).

FIG. 57 is the rnFATP1 protein sequence (SEQ ID NO:59).

FIG. 58A, 58B, and 58C are the rnFATP2 DNA sequence (SEQ ID NO:60).Coding region: 795-2657 (1863 nt).

FIG. 59 is the rnFATP2 protein sequence (SEQ ID NO:61).

FIG. 60A and 60B are the rnFATP4 partial DNA sequence (SEQ ID NO:62).Coding region: 1-1218.

FIG. 61 is the mFATP4 partial DNA sequence (SEQ ID NO:63).

FIG. 62A, 62B, and 62C are the mmFATP1 DNA sequence (SEQ ID NO:64).Coding region: 1-1944.

FIG. 63 is the mmFATP1 protein sequence (SEQ ID NO:65).

FIGS. 64A and 64B are the mmFATP2 DNA sequence (SEQ ID NO:66). Codingregion: 121-1992 (1872 nt).

FIG. 65 is the mmFATP2 protein sequence (SEQ ID NO:67).

FIGS. 66A and 66B are the mmFATP3 partial DNA sequence (SEQ ID NO:68).Coding region: 1-1830.

FIG. 67 is the mmFATP3 partial protein sequence (SEQ ID NO:69).

FIGS. 68A, 68B, and 68C are the mmFATP4 DNA sequence (SEQ ID NO:70).Coding region: 1-1932.

FIG. 69 is the mmFATP4 protein sequence (SEQ ID NO:71).

FIGS. 70A and 70B are the mmFATP5 DNA sequence (SEQ ID NO:72). Codingregion: 60-2129.

FIG. 71 is the mmFATP5 protein sequence (SEQ ID NO:73).

FIGS. 72A and 72B are the dmFATP partial DNA sequence (dm=Drosophilamelanogaster; SEQ ID NO: 74). Coding region: 1-1773.

FIG. 73 is the dmFATP partial protein sequence (SEQ ID NO:75).

FIG. 74 is the drFATP partial DNA sequence (dr=Danio rerio, zebrafish;SEQ ID NO:76) Coding region: 1-173.

FIG. 75 is the drFATP partial protein sequence (SEQ ID NO:77).

FIG. 76A and 76B are the ceFATPa DNA sequence (SEQ ID NO:78). Codingregion: 1-1953.

FIG. 77 is the ceFATPa protein sequence (SEQ ID NO:79).

FIGS. 78A and 78B are the ceFATPb DNA sequence (SEQ ID NO:80). Codingregion: 1-1968.

FIG. 79 is the ceFATPb protein sequence (SEQ ID NO:81).

FIGS. 80A and 80B are the chFATP DNA sequence (SEQ ID NO:82;ch=Cochliobolu heterostrophus). Coding region: 1-1932.

FIG. 81 is the chFATP protein sequence (SEQ ID NO:83).

FIG. 82 is the anFATP partial protein sequence (an=Aspergillus nidulans;SEQ ID NO:84). Coding region: 1-597.

FIG. 83 is the anFATP partial protein sequence (SEQ ID NO:85).

FIG. 84 is the mgFATP partial DNA sequence (mg=Magnaporthe grisea, riceblast; SEQ ID NO:86). Coding region: 1-522.

FIG. 85 is the mgFATP partial protein sequence (SEQ ID NO:87).

FIGS. 86A and 86B are the scFATP DNA sequence (SEQ ID NO:88). Codingregion: 1-1872.

FIG. 87 is the scFATP protein sequence (SEQ ID NO:89).

FIGS. 88A and 88B are the mtFATP DNA sequence (SEQ ID NO:90).

FIG. 89 is the mtFATP protein sequence (SEQ ID NO:91). Coding region:1-1794.

FIG. 90 is a concensus sequence of the FATP signature sequence (SEQ IDNO: 100), based on 23 independent sequences aligned in ClustalX. Theheight of the bar at each amino acid residue position indicates thedegree of conservation at that position. Gaps have been inserted tomaintain the strength of the alignment.

FIG. 91 is a hydrophilicity plot for hsFATP2, made using theKyte-Doolittle method, averaging hydrophilicity values for 18 amino acidresidues at a time.

FIG. 92 is a hydrophilicity plot for the hsFATP3 partial protein, madeusing the Kyte-Doolittle method, averaging hydrophilicity values for 18amino acid residues at a time.

FIG. 93 is a hydrophilicity plot for the hsFATP5 partial protein, madeusing the Kyte-Doolittle method, averaging hydrophilicity values for 18amino acid residues at a time.

FIGS. 94A and 94B are a representation of the DNA sequence (SEQ IDNO:101) of the hsFATP3 gene, and the amino acid sequence (SEQ ID NO:102) of the hsFATP3 protein.

DETAILED DESCRIPTION OF THE INVENTION

As described herein, FATPs are a large evolutionarily conserved familyof proteins that mediate the transport of LCFAs into cells. The familyincludes proteins which are conserved from mycobacteria to humans andexhibit very different expression patterns in tissues. Specificembodiments described include FATPs from mice, humans, nematodes, fungiand mycobacteria which have been shown to be functional LCFAtransporters. The term “fatty acid transport proteins” (“FATPs”) as usedherein, refers to the proteins described herein as FATP1, FATP2, FATP3,FATP4, FATP5 and FATP6, which have been described in one or more speciesof mammals, as well as mtFATP, ceFATP, scFATP, anFATP, mgFATP, andchFATP, and other proteins sharing at least about 50% amino acidsequence similarity, preferably at least about 60% sequence similarity,more preferably at least about 70% sequence similarity, and still morepreferably, at least about 80% sequence similarity, and most preferably,at least about 90% sequence similarity in the approximately 360 aminoacid signature sequence. The approximaely 360 amino acid FATP signaturesequence is shown in FIG. 1. The concensus sequence of the signaturesequence is shown in FIG. 90. The nomenclature used herein to refer toFATPs includes a species-specific prefix (e.g., mm, Mus musculus; hs orh, Homo sapiens or human; mt M. tuberculosis; dm. D. melanogaster; ce,C. elegans; sc, Saccharomyces cerevisiae) and a number such thatmammalian homologues in different species share the same number. Forexample, six human and five mouse FA TP genes which are expressed in avariety of tissues are described herein and are referred to,respectively, as hsFATP1-hsFATP6 and mmFATP1-mmFATP5; for example,hsFATP4 and mmFATP4 are the human and mouse orthologs.

Expression patterns of human and mouse FATPs have been assessed and aredescribed below. Briefly, results of these assessments show that FATP5is a liver-specific gene. FATP2 is highly expressed in liver and kidney.Both of these proteins, as well as FATP4 and FATPs from nematodes andmycobacteria, have been shown to be functional LCFA transporters.Results have also shown that FATP4 mRNA is present at high levels inepithelial cells of two regions of the small intestine (the jejunum andileum) and at lower, but significant, levels in a third region (theduodenum). They further showed that FATP2 mRNA is present in epithelialcells of the duodenum at a level similar to that of FATP4 mRNA levels,but is present at lower levels in the jejunum and ileum. FATP4 mRNA wasabsent from other cell types of the small intestine and no FATP4 mRNAcould be detected in any cells of the colon. No signals above backgroundcould be detected for FATP1, FATP3 and FATP5 in any of the intestinaltissues. Thus, FATP4 is the major FATP in the mouse small intestine,which supports a major role for FATP4 (along with FATP2 to a lesserextent) in absorption of free fatty acids. hsFATP4 was clearly expressedin the jejunum and ileum; expression was absent in the stomach. This,too, is consistent with a major role for FATP4 in absorption of fattyacids in the human gut. Analysis of FATP expression in human tissues,also described in detail below, showed that hsFATP6, which has no mouseortholog as yet, is expressed at high levels in the heart and at lowlevels in the placenta, but is undetectable in the other tissuesassessed (Example 9). This is consistent with a major role for FATP6 inabsorption of fatty acids in the heart.

Long chain fatty acids (LCFAs) are an important energy source for pro-and eukaryotes and are involved in diverse cellular processes, such asmembrane synthesis, intracellular signaling, protein modification, andtranscriptional regulation. In developed Western countries, humandietary lipids are mainly di- and triglycerides and account forapproximately 40% of caloric intake (Weisburger, J. H. (1997) J Am.Diet. Assoc. 97:S16-S23). These lipids are broken down into fatty acidsand glycerol by pancreatic lipases in the small intestine (Chapus, C.,Rovery, M., Sarda, L & Verger, R. (1988) Biochimie 70:1223-34); LCFAsare then transported into brush border cells, where the majority isre-esterified and secreted into the lymphatic system as chylomicrons(Green, P. H. & Riley, J. W. (1981) Aust. N. Z. J. Med. 11:84-90). Fattyacids are liberated from lipoproteins by the enzyme lipoprotein lipase,which is bound to the luminal side of endothelial cells (Scow, R. O. &Blachette-Mackie, E. J. (1992) Mol. Cell. Biochem 116:181-191). “Free”fatty acids in the circulation are bound to serum albumin (Spector, A.A. (1984) Clin. Physiol. Biochem 2:123-134) and are rapidly incorporatedby adipocytes, hepatocytes, and cardiac muscle cells. The latter derive60-90% of their energy through the oxidation of LCFAs (Neely, J. F.Rovetto, M. J. & Oram, J. F. (1972) Prog. Cardiovasc. Dis: 15:289-329).Although saturable and specific uptake of LCFAs has been demonstratedfor intestinal cells, hepatocytes, cardiac myocytes, and adipocytes, themolecular mechanisms of LCFA transport across the plasma membrane haveremained controversial (Hui, T. Y. & Bemlohr, D. A. (1997) Front.Biosci. 15:d222-31-d231; Schaffer, J. E. & Lodish, H. F, (1995) TrendsCardiovasc. Med. 5:218-224). Described herein is a large family ofhighly homologous mammalian LCFA transporters which show wideexpression, including in all tissues relevant to fatty acid metabolism.Further described are novel members of this family in other species,including mycobacterial and nematode FATPs which, like their mammaliancounterparts, are functional fatty acid transporters.

The discovery of a diverse but highly homologous family of FATPs isreminiscent of the glucose transporter family. In a manner similar tothe FATPs, the glucose transporters have very divergent patterns oftissue expression (McGowan, K. M., Long, S. D. & Pekala, P. H. (1995)Pharmacol. Ther. 66:465-505). The FATPs, like glucose transporters, mayalso differ in their substrate specificities, uptake kinetics, andhormonal regulation (Thorens, B. (1996) Am. J Physiol. 270:G541-G553).Indeed, the levels of fatty acids in the blood, like those of glucose,can be regulated by insulin and are dysregulated in diseases such asnoninsulin-dependent diabetes and obesity (Boden, G. (1997) Diabetes46:3-10). The underlying mechanisms for the regulation of free fattyacid concentrations in the blood are not understood, but could beexplained by hormonal modulation of FATPs.

Insulin-resistance is thought to be the major defect in noninsulin-dependent diabetes mellitus (NIDDM) and is one of the earliestmanifestations of NIDDM (McGarry (1992) Science 258:766-770). Free fattyacids (FFAs) may provide an explanation for why obesity is a risk factorfor NIDDM. Plasma levels of FFAs are elevated in diabetic patients(Reaven et al. (1988) Diabetes 37:1020). Elevated plasma free fattyacids (FFAs) have been demonstrated to induce insulin-resistance inwhole animals and humans (Boden (1998) Front. Biosci. 3:D169-D175). Thisinsulin-resistance is likely mediated by effects of FFAs on a variety ofissues. FFAs added to adipocytes in vitro induce insulin resistance inthis cell type as evidenced by inhibition of insulin-induced glucosetransport (Van Epps-Fung et al. (1997) Endocrinology 138:4338-4345).Rats fed a high fat diet developed skeletal muscle insulin resistance asevidenced by a decrease in insulin-induced glucose uptake by skeletalmuscle (Han et al., (1997) Diabetes 46:1761-1767). In addition, elevatedplasma FFAs increase insulin-suppressed endogenous glucose production inthe liver (Boden (1998) Front. Biosci. 3:D169-D175), thus increasinghepatic glucose output. It has been postulated that the adverse effectsof plasma free fatty acids are due to the FFAs being taken up into thecell, leading to an increase in intracellular long chain fatty acyl CoA;intracellular long chain acyl CoAs are thought to mediate the effects ofFFAs inside the cell. Thus, fatty acid induced insulin-resistance may beprevented by blocking uptake of FFAs into select tissues, in particularliver (by blocking FATP2 and/or FATP5), adipocyte (by blocking FATP1),and skeletal muscle (by blocking FATP1). Blocking intestinal fatabsorption (by blocking FATP4) is also expected to reduce plasma FFAlevels and thus improve insulin resistance.

During the pathogenesis of NIDDM insulin-resistance can initially becounteracted by increasing insulin output by the pancreatic beta cell.Ultimately, this compensation fails, beta cell function decreases andovert diabetes results (McGarry (1992) Science 258: 766-770).Manipulating beta cell function is a second point where fatty acidtransporter blockers may be beneficial for diabetes. While no FATPhomolog has been identified so far that is expressed in the beta cell ofthe pancreas, the data described below suggest the existence of such atransporter and the sequence information included herein provides themeans to identify such a transporter by degenerate PCR, using primers toregions conserved in all FATP family members or by low stringencyhybridization. It has been demonstrated that exposure of pancreaticbeta-cells to FFAs increases the basal rate of insulin secretion; thisin turn leads to a decrease in the intracellular stores of insulin,resulting in decreased capacity for insulin secretion after chronicexposure (Bollheimer et al., (1998) J. Clin. Invest. 101:1094-1101). Theeffects of FFAs are again likely to be mediated by intracellular longchain fatty acyl CoA molecules (Liu et al., (1998) J. Clin. Invest.101:1870-1875). FFAs have also been demonstrated to increase beta cellapoptosis (Shimabukuro et al., (1998) Proc. Nat. Acad. Sci. USA95:2498-2502), possibly contributing to the decrease in beta cellnumbers in late stage NIDDM.

Another finding with potentially broad implications is theidentification of a FATP homologue in M. tuberculosis. Tuberculosiscauses more deaths worldwide than any other infectious agent anddrug-resistant tuberculosis is re-emerging as a problem inindustrialized nations (Bloom, B. R. & Small, P. M. (1998) N. Engl. J.Med. 338:677-678). Mycobacterium tuberculosis has about 250 enzymesinvolved in fatty acid metabolism, compared with only about 50 in E.coli. It has been suggested that, living as a pathogen, the mycobacteriaare largely lipolytic, rather than lipogenic, relying on the lipdswithin mammalian cells and the tubercle (Cole, S. T. et al.,Nature393:537-544 (1998)). The de novo synthesis of fatty acids inMycobacterium leprae is insufficient to maintain growth (Wheeler, P. R.,Bulmer, K & Ratledge, C. (1990) J. Gene. Microbiol. 136:211-217). Thus,it is reasonable to expect that inhibitors of mtFATP will serve astherapeutics for tuberculosis. FATPs expressed in mycobacteria can betargeted to reduce or prevent replication of mycobacteria (e.g., toreduce or prevent replication of M. tuberculosis) and, thus, reduce orprevent their adverse effects. For example, a FATP or FATPs expressed byM. tuberculosis can be targeted and inhibited, thus reducing orpreventing growth of this pathogen (and tuberculosis in humans and othermammals). An inhibitor of an M. tuberculosis FATP can be identified,using methods described herein (e.g., expressing the FATP in anappropriate host cell, such as E. coli or COS cells; contacting thecells with an agent or drug to be assessed for its ability to inhibitthe FATP and, as a result, mycobacterial growth, and assessing itseffects on growth). A drug or agent identified in this manner can befurther tested for its ability to inhibit a M. tuberculosis FATP and M.tuberculosis infection in an appropriate animal model or in humans. Amethod of inhibiting mycobacterial growth, particularly growth of M.tuberculosis, and compounds useful as drugs for doing so are also thesubject of this invention.

An isolated polynucleotide encoding mtFATP, like other polynucleotidesencoding FATPs of the FATP family, can be incorporated into vectors,nucleic acids of viruses, and other nucleic acid constructs that can beused in various types of host cells to produce mtFATP. This mtFATP canbe used, as it appears on the surface of cells, or in various artificialmembrane systems, to assess fatty acid transport function, to identifyligands and molecules that are modulators of fatty acid transportactivity. Molecules found to be inhibitors of mtFATP function can beincorporated into pharmaceutical compositions to administer to a humanfor the treatment of tuberculosis.

Particular embodiments of the invention are polynucleotides encoding aFATP of Cochliobolus (Helminthosporium) heterostrophus or portions orvariants thereof, the isolated or recombinantly produced FATP, methodsfor assessing whether an agent binds to the chFATP, and further methodsfor assessing the effect of an agent being tested for its ability tomodulate fatty acid transport activity. Cochliobolus heterostrophus isan ascomycete that is the cause of southern corn leaf blight, aneconomically important threat to the corn crop in the United States. Therelated species C. sativus causes crown rot and common root rot in wheatand barley. One or more FATPs of C. heterostrophus can be targeted forthe identification of an inhibitor of chFATP function, which can be thenbe used as an agent effective against infection of plants by C.heterostrophus and related organisms. Methods described herein that wereapplied in studying the expression of a FATP gene and the function ofthe FATP in its natural site of expression or in a host cell, can beused in the study of the chFATP gene and protein.

Magnaporthe grisea (rice blast) is an economically important fungalpathogen of rice. Further embodiments of the invention are nucleic acidmolecules encoding a FATP of Magnaporthe grisea, portions thereof, orvariants thereof, isolated mgFATP, nucleic acid constructs, andengineered cells expressing mgFATP. Other aspects of the invention areassays to identify an agent which binds to mgFATP and assays to identifyan agent which modulates the function of mgFATP in cells in which mgFATPis expressed or in artificial membrane systems. Agents identified asinhibiting mgFATP activity can be developed into anti-fungal agents tobe used to treat rice infected with rice blast.

Caenorhabditis elegans is a nematode related to plant pathogens andhuman parasites. An isolated polynucleotide which encodes ceFATP, likeother polynucleotides encoding FATPs of the FATP family describedherein, can be incorporated into nucleic acid vectors and otherconstructs that can be used in various types of cells to produce ceFATP.ceFATP as it occurs in cells or as it can be isolated or incorporatedinto various artificial or reconstructed membrane systems, can be usedto assess fatty acid transport, and to identify ligands and agents thatmodulate fatty acid transport activity. Agents found by such assays tobe inhibitors of ceFATP activity can be incorporated into compositionsfor the treatment of diseases caused by genetically related organismswith a FATP of similar sensitivity to the agents.

Aspergillus nidulans is one of a family of fungal species that caninfect humans. Further embodiments of the invention of the family ofpolynucleotides encoding FATPs are polynucleotides encoding a FATP ofAspergillus nidulans, and vectors and host cells that can be constructedto comprise such polynucleotides. Further embodiments are a polypeptideencoded by such polynucleotides, portions thereof having one or morefunctions characteristic of a FATP, and various methods. The methodsinclude those for identifying agents that bind to anFATP and those forassessing the effect of an agent being tested for its ability tomodulate fatty acid transport activity. Those agents found to inhibitfatty acid transport function can be used in compositions as anti-fungalpharmaceuticals, or can be modified for greater effectiveness as apharmaceutical.

One aspect of the invention relates to isolated nucleic acids thatencode a FATP as described herein, such as those FATPs having an aminoacid sequence in FIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49(SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS. 94A and 94B (SEQ IDNO:102), and FIG. 55 (SEQ ID NO:57) and nucleic acids closely relatedthereto as described herein.

Using the information provided herein, such as a nucleic acid sequenceset forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS. 46A and 46B (SEQ IDNO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94Aand 94B (SEQ ID NO: 101), and FIGS. 54A-54C (SEQ ID NO:56), a nucleicacid of the invention encoding a FATP polypeptide may be obtained usingstandard cloning and screening methods, such as those for cloning andsequencing cDNA library fragments, followed by obtaining a full lengthclone. For example, to obtain a nucleic acid of the invention, a libraryof clones of cDNA of human or other mammalian DNA can be probed with alabeled oligonucleotide, such as a radiolabeled oligonucleotide,preferably about 17 nucleotides or longer, derived from a partialsequence. Clones carrying DNA identical to that of the probe can then bedistinguished using stringent (also, “high stringency”) hybridizationconditions. By sequencing the individual clones thus identified withsequencing primers designed from the original sequence it is thenpossible to extend the sequence in both directions to determine the fulllength sequence. Suitable techniques are described, for example, inCurrent Protocols in Molecular Biology (F. M. Ausubel et al, eds),containing supplements through Supplement 42, 1998, John Wiley and Sons,Inc., especially chapters 5, 6 and 7.

Embodiments of the invention include isolated nucleic acid moleculescomprising any of the following nucleotide sequences: 1.) a nucleotidesequence which encodes a protein comprising the amino acid sequence ofhsFATP I (SEQ ID NO:47), the amino acid sequence of hsFATP2 (SEQ IDNO:49), the amino acid sequence of hsFATP3 (SEQ ID NO:102), the aminoacid sequence of hsFATP4 (SEQ ID NO: 53), the amino acid sequence ofhsFATP5 (SEQ ID NO:55) or the amino acid sequence of hsFATP6 (SEQ IDNO:57); 2.) nucleotide sequences of hsFATP1, hsFATP2, hsFATP3, hsFATP4,hsFATP5, or hsFATP6 (SEQ ID NO:46, 48, 101, 52, 54, or 56,respectively); 3.) a nucleotide sequence which is complementary to thenucleotide sequence of hsFATP1 (SEQ ID NO:46), hsFATP2 (SEQ ID NO:48),hsFATP3 (SEQ ID NO:101), hsFATP4 (SEQ ID NO:52), hsFATP5 (SEQ ID NO:54)or hsFATP6 (SEQ ID NO:56); 4.) a nucleotide sequence which consists ofthe coding region of hsFATP1 (SEQ ID NO:46), the coding region ofhsFATP2 (SEQ ID NO:48), the coding region of hsFATP3 (SEQ ID NO:101),the coding region of hsFATP4 (SEQ ID NO:52), the coding region ofhsFATP5 (SEQ ID NO: 54), or the coding region of hsFATP6 (SEQ ID NO:56).

The invention further relates to nucleic acids (nucleic acid moleculesor polynucleotides) having nucleotide sequences identical over theirentire length to those shown in the figures, for instance FIGS. 44A-44C(SEQ ID NO:46), FIGS. 46A and 46B (SEQ ID NO:48), FIG. 48 (SEQ IDNO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A and 94B (SEQ ID NO:101),and FIGS. 54A-54C (SEQ ID NO:56). It further relates to DNA, which dueto the degeneracy of the genetic code, encodes a FATP encoded by one ofthe FATP-encoding DNAs, whose amino acid sequence is provided herein.Also provided by the invention are nucleic acids having the codingsequences for the mature polypeptides or fragments in reading frame withother coding sequences, such as those encoding a leader or secretorysequence, a pre-, or pro- or prepro- protein sequence. The nucleic acidsof the invention encompass nucleic acids that include a singlecontinuous region or discontinuous regions encoding the polypeptide,together with additional regions, that may also contain coding ornon-coding sequences. The nucleic acids may also contain non-codingsequences, including, for example, but not limited to, non-coding 5′ and3′ sequences, such as the transcribed, non-translated sequences,termination signals, ribosome binding sites, sequences that stabilizemRNA, introns, polyadenylation signals, and additional coding sequenceswhich encode additional amino acids. For example, a marker sequence thatfacilitates purification of the fused polypeptide can be encoded. Incertain embodiments of the invention, the marker sequence can be ahexa-histidine peptide, as provided in the pQE vector (Qiagen, Inc.) anddescribed in Gentz et al., Proc. Natl. Acad. Sci. USA 86: 821-824(1989), or an HA tag (Wilson et al., Cell 37: 767 (1984)), or a sequenceencoding glutathione S-transferase of Schistosoma japonicum (vectorsavailable from Pharmacia; see Smith, D. B. and Johnson K. S., Gene 67:31(1988) and Kaelin, W. G. et al., Cell 70:351 (1992)). Nucleic acids ofthe invention also include, but are not limited to, nucleic acidscomprising a structural gene and its naturally associated sequences thatcontrol gene expression.

The invention further relates to variants, including naturally-occurringallelic variants, of those nucleic acids described specifically hereinby DNA sequence, that encode variants of such polypeptides as thosehaving the amino acid sequences shown in FIG. 45 (SEQ ID NO:47), FIG. 47(SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53) FIGS. 94Aand 94B (SEQ ID NO: 102), or FIG. 55 (SEQ ID NO:57). Such variantsinclude nucleic acids encoding variants of the above-listed amino acidsequences, wherein those variants have several, such as 5 to 10, 1 to 5,or 3, 2 or 1 amino acids substituted, deleted, or added, in anycombination. Variants include polynucleotides encoding polypeptides withat least 95% but less than 100% amino acid sequence identity to thepolypeptides described herein by amino acid sequence. Variantpolynucleotides hybridize, under low to high stringency conditions, tothe alleles described herein by DNA sequence. In one embodiment,variants have silent substitutions, additions and deletions that do notalter the properties and activities of the FATP. Allelic variants of thepolynucleotides encoding hsFATP1 (FIG. 45; SEQ ID NO:47), hsFATP2 (FIG.47; SEQ ID NO:49), hsFATP3 (FIGS. 94A and 94B; SEQ ID NO:102), hsFATP4(FIG. 51; SEQ ID NO:53), FIG. 53 (SEQ ID NO:55) and hsFATP6 (FIG. 55;SEQ ID NO:57) will be identified as mapping to chromosomal locationslisted for the corresponding wild type genes in Table 2 in Example 1.

Orthologous genes are gene loci in different species that aresufficiently similar to each other in their nucleotide sequences tosuggest that they originated from a common ancestral gene. Orthologousgenes arise when a lineage splits into two species, rather than when agene is duplicated within a genome. Proteins that are orthologs areencoded by genes of two different species, wherein the genes are said tobe orthologous.

The invention further relates to polynucleotides encoding polypeptideswhich are orthologous to those polypeptides having a specific amino acidsequence described herein, such as the amino acid sequences shown inFIG. 45 (SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51),FIG. 51 (SEQ ID NO:53), FIGS. 94A and 94B (SEQ ID NO: 102), or FIG. 55(SEQ ID NO:57). These polynucleotides, which can be called orthologpolynucleotides, encode orthologous polypeptides that can range in aminoacid sequence identity to a reference amino acid sequence describedherein, from about 65% to less than 100%, but preferably 70% to 80%,more preferably 80% to 90%, and still more preferably 90% to less than100%. Orthologous polypeptides can also be those polypeptides that rangein amino acid sequence similarity to a reference amino acid sequencedescribed herein from about 75% to 100%, within the signature sequence.The amino acid sequence similarity between the signature sequences oforthologous polypeptides is preferably 80%, more preferably 90%, andstill more preferably, 95%. The ortholog polynucleotides encodepolypeptides that have similar functional characteristics (e.g., fattyacid transport activity) and similar tissue distribution, as appropriateto the organism from which the ortholog polynucleotides can be isolated.

Ortholog polynucleotides can be isolated from (e.g., by cloning ornucleic acid amplification methods) a great number of species, as shownby the sample of FATPs from evolutionarily divergent species describedherein (see, e.g., FIGS. 44A-C through FIG. 89). Orthologpolynucleotides corresponding to those in FIG. 45 (SEQ ID NO:47), FIG.47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQ ID NO:53), FIGS.94A and 94B (SEQ ID NO: 102) and FIG. 55 (SEQ ID NO:57) are those whichcan be isolated from mammals such as rat, dog, chimpanzee, monkey,baboon, pig, rabbit and guinea pig, for example.

Further variants that are fragments of the nucleic acids of theinvention may be used to synthesize full-length nucleic acids of theinvention, such as by use as primers in a polymerase chain reaction. Asused herein, the term primer refers to a single-stranded oligonucleotidewhich acts as a point of initiation of template-directed DNA synthesisunder appropriate conditions (e.g., in the presence of four differentnucleoside triphosphates and an agent for polymerization, such as DNA orRNA polymerase or reverse transcriptase) in an appropriate buffer and ata suitable temperature. The appropriate length of a primer depends onthe intended use of the primer, but typically ranges from 15 to 30nucleotides. Short primer molecules generally require coolertemperatures to form sufficiently stable hybrid complexes with thetemplate. A primer need not reflect the exact sequence of the template,but must be sufficiently complementary to hybridize with a template. Theterm primer site refers to the area of the target DNA to which a primerhybridizes. The term primer pair refers to a set of primers including a5′ (upstream) primer that hybridizes with the 5′ end of the DNA sequenceto be amplified and a 3′ (downstream) primer that hybridizes with thecomplement of the 3′ end of the sequence to be amplified.

Further embodiments of the invention are nucleic acids that are at least80% identical over their entire length to a nucleic acid describedherein, for example a nucleic acid having the nucleotide sequence inFIGS. 44A-44C (SEQ ID NO:46), FIGS. 46A-46B (SEQ ID NO:48), FIG. 48 (SEQID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94A and 94B (SEQ IDNO:l01), and FIGS. 54A-54C (SEQ ID NO:56). Additional embodiments arenucleic acids, and the complements of such nucleic acids, having atleast 90% nucleotide sequence identity to the above-described sequences,and nucleic acids having at least 95% nucleotide sequence identity. Inpreferred embodiments, DNA of the present invention has 97% nucleotidesequence identity, 98% nucleotide sequence identity, or at least 99%nucleotide sequence identity with the DNA whose sequences are presentedherein.

Other embodiments of the invention are nucleic acids that are at least80% identical in nucleotide sequence to a nucleic acid encoding apolypeptide having an amino acid sequence as set forth in FIG. 45 (SEQID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51 (SEQID NO:53), FIGS. 94A and 94B (SEQ ID NO:102) or FIG. 55 (SEQ ID NO:57),or as such amino acid sequences are set forth elsewhere herein, andnucleic acids that are complementary to such nucleic acids. Specificembodiments are nucleic acids having at least 90% nucleotide sequenceidentity to a nucleic acid encoding a polypeptide having an amino acidsequence as described in the list above, nucleic acids having at least95% sequence identity, and nucleic acids having at least 97% sequenceidentity.

The terms “complementary” or “complementarity” as used herein, refer tothe natural binding of polynucleotides under permissive salt andtemperature conditions by base-pairing. Complementarity between twosingle-stranded molecules may be “partial” in which only some of thenucleic acids bind, or it may be complete when total complementarityexists between the single-stranded molecules (that is, when A-T and G-Cbase pairing is 100% complete). The degree of complementarity betweennucleic acid strands has significant effects on the efficiency andstrength of hybridization between nucleic acid strands. This is ofparticular importance in amplification reactions, which depend onbinding between nucleic acid strands.

The invention further includes nucleic acids that hybridize to theabove-described nucleic acids, especially those nucleic acids thathybridize under stringent hybridization conditions. “Stringenthybridization conditions” or “high stringency conditions” generallyoccur within a range from about T_(m) minus 5° C. (50° C. below thestrand dissociation temperature or melting temperature (T_(m)) of theprobe nucleic acid molecule) to about 20° C. to 25° C. below T_(m). Aswill be understood by those of skill in the art, the stringency ofhybridization may be altered in order to identify or detect moleculeshaving identical or related polynucleotide sequences. An example of highstringency hybridization follows. Hybridization solution is (6×SSC/10 mMEDTA/0.5% SDS/5×Denhardt's solution/100 μg/ml sheared and denaturedsalmon sperm DNA). Hybridization is at 64-65° C. for 16 hours. Thehybridized blot is washed two times with 2×SSC/0.5% SDS solution at roomtemperature for 15 minutes each, and two times with 0.2×SSC/0.5% SDS at65° C., for one hour each. Further examples of high stringencyconditions can be found on pages 2.10.1-2.10.16 (see particularly2.10.8-11) and pages 6.3.1-6 in Current Protocols in Molecular Biology(Ausubel, F. M. et al., eds., containing supplements up throughSupplement 42, 1998). Examples of high, medium, and low stringencyconditions can be found on pages 36 and 37 of WO 98/40404, which areincorporated herein by reference.

The invention further relates to nucleic acids obtainable by screeningan appropriate library with a probe having a nucleotide sequence such asthat set forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS. 46A-46B (SEQ IDNO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ ID NO:52), FIGS. 94Aand 94B (SEQ ID NO:101) or FIGS. 54A-54C (SEQ ID NO:56), or a probewhich is a sufficiently long fragment of any of the above; and isolatingthe nucleic acid. Such probes generally can comprise at least 15nucleotides. Nucleic acids obtainable by such screenings may includeRNAs, cDNAs and genomic DNA, for example, encoding FATPs of the FATPfamily described herein.

Further uses for the nucleic acid molecules of the invention, whetherencoding a full-length FATP or whether comprising a contiguous portionof a nucleic acid molecule such as one given in SEQ ID NO:46, 48, 50,52, 101, or 56, include use as markers for tissues in which thecorresponding protein is preferentially expressed (to identifyconstitutively expressed proteins or proteins produced at a particularstage of tissue differentiation or stage of development of a diseasestate); as molecular weight markers on southern gels; as chromosomemarkers or tags (when labeled, for example with biotin, a radioactivelabel or a fluorescent label) to identify chromosomes or to map relatedgene positions; to compare with endogenous DNA sequences in a mammal toidentify potential genetic disorders; as probes to hybridize and thusidentify, related DNA sequences; as a source of information to derivePCR primers for genetic fingerprinting; as a probe to “subtract-out”known sequences in the process of discovering other novel nucleic acidmolecules; for selecting and making oligomers for attachment to a “genechip” or other support, to be used, for example, for examination ofexpression patterns; to raise anti-protein antibodies using DNAimmunization techniques; and as an antigen to raise anti-DNA antibodiesor to elicit another immune response.

Further methods to obtain nucleic acids encoding FATPs of the FATPfamily include PCR and variations thereof (e.g., “RACE” PCR andsemi-specific PCR methods). Portions of the nucleic acids having anucleotide sequence set forth in FIGS. 44A-44C (SEQ ID NO:46), FIGS.46A-46B (SEQ ID NO:48), FIG. 48 (SEQ ID NO:50), FIGS. 50A-50C (SEQ IDNO:52), FIGS. 94A and 94B (SEQ ID NO: 101) or FIGS. 54A-54C (SEQ IDNO:56), (especially “flanking sequences” on either side of a codingregion) can be used as primers in methods using the polymerase chainreaction, to produce DNA from an appropriate template nucleic acid.

Once a fragment of the FATP gene is generated by PCR, it can besequenced, and the sequence of the product can be compared to other DNAsequences, for example, by using the BLAST Network Service at theNational Center for Biotechnology Information. The boundaries of theopen reading frame can then be identified using semi-specific PCR orother suitable methods such as library screening. Once the 5′ initiatormethionine codon and the 3′ stop codon have been identified, a PCRproduct encoding the full-length gene can be generated using genomic DNAas a template, with primers complementary to the extreme 5′ and 3′ endsof the gene or to their flanking sequences. The full-length genes canthen be cloned into expression vectors for the production of functionalproteins.

The invention also relates to isolated proteins or polypeptides such asthose encoded by nucleic acids of the present invention. Isolatedproteins can be purified from a natural source or can be maderecombinantly. Proteins or polypeptides referred to herein as “isolated”are proteins or polypeptides that exist in a state different from thestate in which they exist in cells in which they are normally expressedin an organism, and include proteins or polypeptides obtained by methodsdescribed herein, similar methods or other suitable methods, and alsoinclude essentially pure proteins or polypeptides, proteins orpolypeptides produced by chemical synthesis or by combinations ofbiological and chemical methods, and recombinant proteins orpolypeptides which are isolated. Thus, the term “isolated” as usedherein, indicates that the polypeptide in question exists in a physicalmilieu distinct from that in which it occurs in nature. Thus, “isolated”includes existing in membrane fragments and vesicles membrane fractions,liposomes, lipid bilayers and other artificial membrane systems. Anisolated FATP may be substantially isolated with respect to the complexcellular milieu in which it naturally occurs, and may even be purifiedessentially to homogeneity, for example as determined by PAGE or columnchromatography (for example, HPLC), but may also have further cofactorsor molecular stabilizers, such as detergents, added to the purifiedprotein to enhance activity. In one embodiment, proteins or polypeptidesare isolated to a state at least about 75% pure; more preferably atleast about 85% pure, and still more preferably at least about 95% pure,as determined by Coomassie blue staining of proteins onSDS-polyacrylamide gels. Proteins or polypeptides referred to herein as“recombinant” are proteins or polypeptides produced by the expression ofrecombinant nucleic acids.

In a preferred embodiment, an isolated polypeptide comprising a FATP, afunctional portion thereof, or a functional equivalent of the FATP, hasat least one function characteristic of a FATP, for example, transportactivity, binding function (e.g., a domain which binds to AMP), orantigenic function (e.g., binding of antibodies that also bind to anaturally-occurring FATP, as that function is found in an antigenicdeterminant). Functional equivalents can have activities that arequantitatively similar to, greater than, or less than, the referenceprotein. These proteins include, for example, naturally occurring FATPsthat can be purified from tissues in which they are produced (includingpolymorphic or allelic variants), variants (e.g., mutants) of thoseproteins and/or portions thereof. Such variants include mutantsdiffering by the addition, deletion or substitution of one or more aminoacid residues, or modified polypeptides in which one or more residuesare modified, and mutants comprising one or more modified residues.Portions or fragments of a FATP can range in size from four amino acidresidues to the entire amino acid sequence minus one amino acid.

The isolated proteins of the invention preferably include mammalianfatty acid transport proteins of the FATP family of homologous proteins.In one embodiment, the extent of amino acid sequence similarity betweena polypeptide having one of the amino acid sequences shown in FIG. 45(SEQ ID NO:47), FIG. 47 (SEQ ID NO:49), FIG. 49 (SEQ ID NO:51), FIG. 51(SEQ ID NO:53), FIGS. 94A and 94B (SEQ ID NO: 102), or FIG. 55 (SEQ IDNO:57), and the respective functional equivalents of these polypeptidesis at least about 88%. In other embodiments, the degree of amino acidsequence similarity between a FATP and its respective functionalequivalent is at least about 91%, at least about 94%, or at least about97%.

The polypeptides of the invention also include those FATPs encoded bypolynucleotides which are orthologous to those polynucleotides, thesequences of which are described herein in whole or in part. FATPs whichare orthologs to those described herein by amino acid sequence, in wholeor in part, are, for example fatty acid transport proteins 1-6 of dog,rat chimpanzee, monkey, rabbit, guinea pig, baboon and pig, and are alsoembodiments of the invention.

To determine the percent identity or similarity of two amino acidsequences or of two nucleic acid sequences, the sequences are alignedfor optimal comparison purposes (e.g., gaps can be introduced in one orboth of a first and a second amino acid or nucleic acid sequence foroptimal alignment, and non-homologous (dissimilar) sequences can bedisregarded for comparison purposes). In a preferred embodiment, thelength of a reference sequence aligned for comparison purposes is atleast 30%, preferably at least 40%, more preferably at least 50%, evenmore preferably at least 60%, and even more preferably at least 70%,80%, or 90% of the length of the reference sequence. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein, amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “similarity”).The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The invention also encompasses polypeptides having a lower degree ofidentity but having sufficient similarity so as to perform one or moreof the same functions performed by the polypeptides described herein byamino acid sequence. Similarity for a polypeptide is determined byconserved amino acid substitution. Such substitutions are those thatsubstitute a given amino acid in a polypeptide by another amino acid oflike characteristics. Conservative substitutions are likely to bephenotypically silent. Typically seen as conservative substitutions arethe replacements, one for another, among the aliphatic amino acids Ala,Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr,exchange of the acidic residues Asp and Glu, substitution between theamide residues Asn and Gln, exchange of the basic residues Lys and Argand replacements among the aromatic residues Phe, Tyr. Guidanceconcerning which amino acid changes are likely to be phenotypicallysilent is found in Bowie et al., Science 247:1306-1310 (1990).

TABLE 1 Conservative Amino Acid Substitutions Aromatic PhenylalanineTryptophan Tyrosine Hydrophobic Leucine Isoleucine Valine PolarGlutamine Asparagine Basic Arginine Lysine Histidine Acidic AsparticAcid Glutamic Acid Small Alanine Serine Threonine Methionine Glycine

The comparison of sequences and determination of percent identity andsimilarity between two sequences can be accomplished using amathematical algorithm. (Computational Molecular Biology, Lesk, A.M.,ed., Oxford University Press, New York, 1988; Biocomputing:Informatics and Genome Projects, Smith, D. W., ed., Academic Press, NewYork, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M.,and Griffin, H. G., eds., Humana Press, New Jersey, 1994; SequenceAnalysis in Molecular Biology, von Heinje, G., Academic Press, 1987; andSequence Analysis Primer, Gribskov, M. and Devereaux, J., eds., M.Stockton Press, New York, 1991). In a preferred embodiment, the percentidentity between two amino acid sequences is determined using theNeedleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm whichhas been incorporated into the GAP program in the GCG software package(available at http://www.gcg.com), using either a Blossom 62 matrix or aPAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and alength weight of 1, 2, 3, 4, 5, or 6. In yet another preferredembodiment, the percent identity between two nucleotide sequences isdetermined using the GAP program in the GCG software package (Devereux,J., et al., Nucleic Acids Res. 12(1):387 (1984)) (available athttp://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Inanother embodiment, the percent identity between two amino acid ornucleotide sequences is determined using the algorithm of E. Meyers andW. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into theALIGN program (version 2.0), using a PAM120 weight residue table, a gaplength penalty of 12 and a gap penalty of 4.

The nucleic acid and protein sequences of the present invention canfurther be used as a “query sequence” to perform a search againstdatabases to, for example, identify other family members or relatedsequences. Such searches can be performed using the NBLAST and XBLASTprograms (version 2.0) of Altschul, et al. (J. Mol. Biol. 215:403-10(1990)). BLAST nucleotide searches can be performed with the NBLASTprogram, score=100, word length=12 to obtain nucleotide sequenceshomologous to (with calculatably significant similarity to) the nucleicacid molecules of the invention. BLAST protein searches can be performedwith the XBLAST program, score=50, word length=3 to obtain amino acidsequences homologous to the proteins of the invention. To obtain gappedalignments for comparison purposes, Gapped BLAST can be utilized asdescribed in Altschul et al., (Nucleic Acids Res. 25(17):3389-3402(1997)). When utilizing BLAST and gapped BLAST programs, the defaultparameters of the respective programs (e.g., XBLAST and NBLAST) can beused. See http://www.ncbi.nlm.nih.gov.

Similarity for nucleotide and amino acid sequences can be defined interms of the parameters set by the Advanced Blast search available fromNCBI (the National Center for Biotechnology Information; see, forAdvanced BLAST page, www.ncbi.nlm.nih.gov/cgi-bin/BLAST/nph-newblast?Jform=1). These default parameters, recommended for a query molecule oflength greater than 85 amino acid residues or nucleotides have been setas follows: gap existence cost, 11, per residue gap cost, 1; lambdaratio, 0.85. Further explanation of version 2.0 of BLAST can be found onrelated website pages and in Altschul, S. F. et al., Nucleic Acids Res.25:3389-3402 (1997).

The invention further relates to fusion proteins, comprising a FATP orfunctional portion thereof (as described above) as a first moiety,linked to second moiety not occurring in the FATP as found in nature.Thus, the second moiety can be an amino acid, peptide or polypeptide.The first moiety can be in an N-terminal location, C-terminal locationor internal to the fusion protein. In one embodiment, the fusion proteincomprises a FATP as the first moiety, and a second moiety comprising alinker sequence and an affinity ligand. Fusion proteins can be producedby a variety of methods. For example, a fusion protein can be producedby the insertion of a FATP gene or portion thereof into a suitableexpression vector, such as Bluescript SK+/−(Stratagene), pGEX-4T-2(Pharmacia), pET-24(+) (Novagen), or vectors of similar construction.The resulting construct can be introduced into a suitable host cell forexpression. Upon expression, fusion protein can be purified from cellsby means of a suitable affinity matrix (See e.g., Current Protocols inMolecular Biology, Ausubel, F. M. et al., eds., Vol. 2, pp.16.4.1-16.7.8, containing supplements up through Supplement 42, 1998).

The invention also relates to enzymatically produced, syntheticallyproduced, or recombinantly produced portions of a fatty acid transportprotein. Portions of a FATP can be made which have full or partialfunction on their own, or which when mixed together (though fully,partially, or nonfunctional alone), spontaneously assemble with one ormore other polypeptides to reconstitute a functional protein having atleast one function characteristic of a FATP.

Fragments of a FATP can be produced by direct peptide synthesis, forexample those using solid-phase techniques (Roberge, J. Y. et al.,Science 269:202-204 (1995); Merrifield, J., J. Am. Chem. Soc.85:2149-2154 (1963)). Protein synthesis can be performed using manualtechniques or by automation. Automated synthesis can be carried outusing, for instance, an Applied Biosystems 43 1A Peptide Synthesizer(Perkin Elmer). Various fragments of a FATP can be synthesizedseparately and combined using chemical methods.

One aspect of the invention is a peptide or polypeptide having the aminoacid sequence of a portion of a fatty acid transport protein which ishydrophilic rather than hydrophobic, and ordinarily can be detected asfacing the outside of the cell membrane. Such a peptide or polypeptidecan be thought of as being an extracellular domain of the FATP, or amimetic of said extracellular domain. It is known, for example, that aportion of human FATP4 that includes a highly conserved motif isinvolved in AMP-CoA binding function (Stuhlsatz-Krouper, S. M. et al.,J. Biol. Chem. 44:28642-28650 (1998)).

The term “mimetic” as used herein, refers to a molecule, the structureof which is developed from knowledge of the structure of the FATP ofinterest, or one or more portions thereof, and, as such, is able toeffect some or all of the functions of a FATP.

Portions of an FATP can be prepared by enzymatic cleavage of theisolated protein, or can be made by chemical synthesis methods. Portionsof a FATP can also be made by recombinant DNA methods in whichrestriction fragments, or fragments that may have undergone furtherenzymatic processing, or synthetically made DNAs are joined together toconstruct an altered FATP gene. The gene can be made such that itencodes one or more desired portions of a FATP. These portions of FATPcan be entirely homologous to a known FATP, or can be altered in aminoacid sequence relative to naturally occurring FATPs to enhance orintroduce desired properties such as solubility, stability, or affinityto a ligand. A further feature of the gene can be a sequence encoding anN-terminal signal peptide directed to the plasma membrane.

An extracellular domain can be determined by a hydrophobicity plot, suchas those shown in FIGS. 28A, 29A, and 35A, or by a hydrophilicity plotsuch as those shown in FIGS. 28C, 29C, 35C, 91, 92 and 93. A polypeptideor peptide comprising all or a portion of a FATP extracellular domaincan be used in a pharmaceutical composition. When administered to amammal by an appropriate route, the polypeptide or peptide can bind tofatty acids and compete with the native FATPs in the membrane of cells,thereby making fewer fatty acid molecules available as substrates fortransport into cells, and reducing the amount of fatty acids taken upby, for example, the heart, in the case of FATP6.

Another aspect of the invention relates to a method of producing a fattyacid transport protein, variants or portions thereof, and to expressionsystems and host cells containing a vector appropriate for expression ofa fatty acid transport protein.

Cells that express a FATP, a variant or a portion thereof, or anortholog of a FATP described herein by amino acid sequence, can be madeand maintained in culture, under conditions suitable for expression, toproduce protein in the cells for cell-based assays, or to produceprotein for isolation. These cells can be procaryotic or eucaryotic.Examples of procaryotic cells that can be used for expression includeEscherichia coli, Bacillus subtilis and other bacteria. Examples ofeucaryotic cells that can be used for expression include yeasts such asSaccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris andother lower eucaryotic cells, and cells of higher eucaryotes such asthose from insects and mammals, such as primary cells and cell linessuch as CHO, HeLa, 3T3 and BHK cells, preferably COS cells and humankidney 293 cells, and more preferably Jurkat cells. (See, e.g., Ausubel,F. M. et al., eds. Current Protocols in Molecular Biology, GreenePublishing Associates and John Wiley & Sons, Inc., containingSupplements up through Supplement 42, 1998)).

In one embodiment, host cells that produce a recombinant FATP, or aportion thereof, a variant, or an ortholog of a FATP described herein byamino acid sequence, can be made as follows. A gene encoding a FATP,variant or a portion thereof can be inserted into a nucleic acid vector,e.g., a DNA vector, such as a plasmid, phage, cosmid, phagemid, virus,virus-derived vector (e.g., SV40, vaccinia, adenovirus, fowl pox virus,pseudorabies viruses, retroviruses) or other suitable replicon, whichcan be present in a single copy or multiple copies, or the gene can beintegrated in a host cell chromosome. A suitable replicon or integratedgene can contain all or part of the coding sequence for a FATP orvariant, operably linked to one or more expression control regionswhereby the coding sequence is under the control of transcriptionsignals and linked to appropriate translation signals to permittranslation. The vector can be introduced into cells by a methodappropriate to the type of host cells (e.g., transfection,electroporation, infection). For expression from the FATP gene, the hostcells can be maintained under appropriate conditions (e.g., in thepresence of inducer, normal growth conditions, etc.). Proteins orpolypeptides thus produced can be recovered (e.g., from the cells, as ina membrane fraction, from the periplasmic space of bacteria, fromculture medium) using suitable techniques. Appropriate membranetargeting signals may be incorporated into the expressed polypeptide.These signals may be endogenous to the polypeptide or they may beheterologous signals.

Polypeptides of the invention can be recovered and purified from cellcultures (or from their primary cell source) by well-known methodsincluding ammonium sulfate or ethanol precipitation, acid extraction,anion or cation exchange chromatography, phosphocellulosechromatography, hydrophobic interaction chromatography, affinitychromatography, hydroxylapatite chromatography and high performanceliquid chromatography. Known methods for refolding protein can be usedto regenerate active conformation if the polypeptide is denatured duringisolation or purification.

In a further aspect of the invention are methods for assessing thetransport function of any of the fatty acid transport proteins orpolypeptides described herein, including orthologs, and in variations ofthese, methods for identifying an inhibitor (or an enhancer) of suchfunction and methods for assessing the transport function in thepresence of a candidate inhibitor or a known inhibitor.

A variety of systems comprising living cells can be used for thesemethods. Cells to be used in fatty acid transport assays, and further inmethods for identifying an inhibitor or enhancer of this function,express one or more FATPs. See Examples 3, 6, 9, 12 and 14 for data ontissue distribution of expression of FATPs, and Examples 10 and 11describing recombinant cells expressing FATP. Cells for use incell-based assays described herein can be drawn from a variety ofsources, such as isolated primary cells of various organs and tissueswherein one or more FATPs are naturally expressed. In some cases, thecells can be from adult organs, and in some cases, from embryonic orfetal organs, such as heart, lung, liver, intestine, skeletal muscle,kidney and the like. Cells for this purpose can also include cellscultured as fragments of organs or in conditions simulating the celltype and/or tissue organization of organs, in which artificial materialsmay be used as substrates for cell growth. Other types of cells suitablefor this purpose include cells of a cell strain or cell line (ordinarilycomprising cells considered to be “transformed”) transfected to expressone or more FATPs.

A further embodiment of the invention is a method for detecting, in asample of cells, a fatty acid transport protein, a portion or fragmentthereof, a fusion protein comprising a FATP or a portion thereof, or anortholog as described herein, wherein the cells can be, for instance,cells of a tissue, primary culture cells, or cells of a cell line,including cells into which nucleic acid has been introduced. The methodcomprises adding to the sample an agent that specifically binds to theprotein, and detecting the agent specifically bound to the protein.Appropriate washing steps can be added to reduce nonspecific binding tothe agent. The agent can be, for example, an antibody, a ligand or asubstrate mimic. The agent can have incorporated into it, or have boundto it, covalently or by high affinity non-covalent interactions, forinstance, a label that facilitates detection of the agent to which it isbound, wherein the label can be, but is not limited to, a phosphorescentlabel, a fluorescent label, a biotin or avidin label, or a radioactivelabel. The means of detection of a fatty acid transport protein canvary, as appropriate to the agent and label used. For example, for anantibody that binds to the fatty acid transport protein, the means ofdetection may call for binding a second antibody, which has beenconjugated to an enzyme, to the antibody which binds the fatty acidtransport protein, and detecting the presence of the second antibody bymeans of the enzymatic activity of the conjugated enzyme.

Similar principles can also be applied to a cell lysate or a morepurified preparation of proteins from cells that may comprise a fattyacid transport protein of interest, for example in the methods ofimmunoprecipitation, immunoblotting, immunoaffinity methods, that inaddition to detection of the particular FATP, can also be used inpurification steps, and qualitative and quantitative immunoassays. See,for instance, chapters 11 through 14 in Antibodies: A Laboratory Manual,E. Harlow and D. Lane, eds., Cold Spring Harbor Laboratory, 1988.

Isolated fatty acid transport protein or, an antigenically similarportion thereof, especially a portion that is soluble, can be used in amethod to select and identify molecules which bind specifically to theFATP. Fusion proteins comprising all of, or a portion of, the fatty acidtransport protein linked to a second moiety not occurring in the FATP asfound in nature, can be prepared for use in another embodiment of themethod. Suitable fusion proteins for this purpose include those in whichthe second moiety comprises an affinity ligand (e.g., an enzyme,antigen, epitope). FATP fusion proteins can be produced by the insertionof a gene encoding the FATP or a variant thereof, or a suitable portionof such gene into a suitable expression vector, which encodes anaffinity ligand (e.g., pGEX-4T-2 and pET-15b, encoding glutathioneS-transferase and His-Tag affinity ligands, respectively). Theexpression vector can be introduced into a suitable host cell forexpression. Host cells are lysed and the lysate, containing fusionprotein, can be bound to a suitable affinity matrix by contacting thelysate with an affinity matrix.

In one embodiment, the fusion protein can be immobilized on a suitableaffinity matrix under conditions sufficient to bind the affinity ligandportion of the fusion protein to the matrix, and is contacted with oneor more candidate binding agents (e.g., a mixture of peptides) to betested, under conditions suitable for binding of the binding agents tothe FATP portion of the bound fusion protein. Next, the affinity matrixwith bound fusion protein can be washed with a suitable wash buffer toremove unbound candidate binding agents and non-specifically boundcandidate binding agents. Those agents which remain bound can bereleased by contacting the affinity matrix with fusion protein boundthereto with a suitable elution buffer. Wash buffer can be formulated topermit binding of the fusion protein to the affinity matrix, withoutsignificantly disrupting binding of specifically bound binding agents.In this aspect, elution buffer can be formulated to permit retention ofthe fusion protein by the affinity matrix, but can be formulated tointerfere with binding of the candidate binding agents to the targetportion of the fusion protein. For example, a change in the ionicstrength or pH of the elution buffer can lead to release of specificallybound agent, or the elution buffer can comprise a release component orcomponents designed to disrupt binding of specifically bound agent tothe target portion of the fusion protein.

Immobilization can be performed prior to, simultaneous with, or after,contacting the fusion protein with candidate binding agent, asappropriate. Various permutations of the method are possible, dependingupon factors such as the candidate molecules tested, the affinitymatrix-ligand pair selected, and elution buffer formulation. Forexample, after the wash step, fusion protein with binding agentmolecules bound thereto can be eluted from the affinity matrix with asuitable elution buffer (a matrix elution buffer, such as glutathionefor a GST fusion). Where the fusion protein comprises a cleavablelinker, such as a thrombin cleavage site, cleavage from the affinityligand can release a portion of the fusion with the candidate agentbound thereto. Bound agent molecules can then be released from thefusion protein or its cleavage product by an appropriate method, such asextraction.

One or more candidate binding agents can be tested simultaneously. Wherea mixture of candidate binding agents is tested, those found to bind bythe foregoing processes can be separated (as appropriate) and identifiedby suitable methods (e.g., PCR, sequencing, chromatography). Largelibraries of candidate binding agents (e.g., peptides, RNAoligonucleotides) produced by combinatorial chemical synthesis or byother methods can be tested (see e.g., Ohlmeyer, M. H. J. et al., Proc.Natl. Acad. Sci. USA 90:10922-10926 (1993) and DeWitt, S. H. et al.,Proc. Natl. Acad. Sci. USA 90:6909-6913 (1993), relating to taggedcompounds; see also Rutter, W. J. et al. U.S. Pat. No. 5,010,175;Huebner, V. D. et al., U.S. Pat. No. 5,182,366; and Geysen, H. M., U.S.Pat. No. 4,833,092). Random sequence RNA libraries (see Ellington, A. D.et al., Nature 346:818-822 (1990); Bock, L. C. et al., Nature355:584-566 (1992); and Szostak, J. W., Trends in Biochem. Sci. 17:89-93(March, 1992)) can also be screened according to the present method toselect RNA molecules which bind to a target FATP or FATP fusion protein.Where binding agents selected from a combinatorial library by thepresent method carry unique tags, identification of individualbiomolecules by chromatographic methods is possible. Where bindingagents do not carry tags, chromatographic separation, followed by massspectrometry to ascertain structure, can be used to identify bindingagents selected by the method, for example.

The invention also comprises a method for identifying an agent whichinhibits interaction between a fatty acid transport protein (e.g., onecomprising the amino acid sequence in SEQ ID NO:47, SEQ ID NO:49, SEQ IDNO:51, SEQ ID NO:53, SEQ ID NO:102, or SEQ ID NO:57), and a ligand ofsaid protein. The FATP can be one described by amino acid sequenceherein, a portion or fragment thereof, a variant thereof, or an orthologthereof, or a FATP fusion protein. Here, a ligand can be, for instance,a substrate, or a substrate mimic, an antibody, or a compound, such as apeptide, that binds with specificity to a site on the protein. Themethod comprises combining, not limited to a particular order, the fattyacid protein, the ligand of the protein, and a candidate agent to beassessed for its ability to inhibit interaction between the protein andthe ligand, under conditions appropriate for interaction between theprotein and the ligand (e.g., pH, salt, temperature conditions conduciveto appropriate conformation and molecular interactions); determining theextent to which the protein and ligand interact; and comparing (1) theextent of protein-ligand interaction in the presence of candidate agentwith (2) the extent of protein-ligand interaction in the absence ofcandidate agent, wherein if (1) is less than (2), then the candidateagent is one which inhibits interaction between the protein and theligand.

The method can be facilitated, for example, by using an experimentalsystem which employs a solid support (column chromatography matrix, wallof a plate, microtiter wells, column pore glass, pins to be submerged ina solution, beads, etc.) to which the protein can be attached.Accordingly, in one embodiment, the protein can be fixed to a solidphase directly or indirectly, by a linker. The candidate agent to betested is added under conditions conducive for interaction and bindingto the protein. The ligand is added to the solid phase system underconditions appropriate for binding. Excess ligand is removed, as by aseries of washes done under conditions that do not disruptprotein-ligand interactions. Detection of bound ligand can befacilitated by using a ligand that carries a label (e.g., fluorescent,chemiluminescent, radioactive). In a control experiment, protein andligand are allowed to interact in the absence of any candidate agent,under conditions otherwise identical to those used for the “test”conditions where candidate inhibiting agent is present, and any washesused in the test conditions are also used in the control. The extent towhich ligand binds to the protein in the presence of candidate agent iscompared to the extent to which ligand binds to the protein in theabsence of the candidate agent. If the extent to which interaction ofthe protein and the ligand occurs is less in the presence of thecandidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits interaction between theprotein and the ligand of the protein.

In a further embodiment, an inhibitor (or an enhancer) of a fatty acidtransport protein can be identified. The method comprises steps whichare, or are variations of the following: contacting the cells with fattyacid, wherein the fatty acid can be labeled for convenience ofdetection; contacting a first aliquot of the cells with an agent beingtested as an inhibitor (or enhancer) of fatty acid uptake whilemaintaining a second aliquot of cells under the same conditions butwithout contact with the agent; and measuring (e.g., quantitating) fattyacid in the first and second aliquots of cells; wherein a lesserquantity of fatty acid in the first aliquot compared to that in thesecond aliquot is indicative that the agent is an inhibitor of fattyacid uptake by a fatty acid transport protein. A greater quantity offatty acid in the first aliquot compared to that in the second aliquotis indicative that the agent is an enhancer of fatty acid uptake by afatty acid transport protein.

A particular embodiment of identifying an inhibitor or enhancer of fattyacid transport function employs the above steps, but also employsadditional steps preceding those given above: introducing into cells ofa cell strain or cell line (“host cells” for the intended introductionof, or after the introduction of, a vector) a vector comprising a fattyacid transport protein gene, wherein expression of the gene can beregulatable or constitutive, and providing conditions to the host cellsunder which expression of the gene can occur.

The terms “contacting” and “combining” as used herein in the context ofbringing molecules into close proximity to each other, can beaccomplished by conventional means. For example, when referring tomolecules that are soluble, contacting is achieved by adding themolecules together in a solution. “Contacting” can also be adding anagent to a test system, such as a vessel containing cells in tissueculture.

The term “inhibitor” or “antagonist”, as used herein, refers to an agentwhich blocks, diminishes, inhibits, hinders, limits, decreases, reduces,restricts or interferes with fatty acid transport into the cytoplasm ofa cell, or alternatively and additionally, prevents or impedes thecellular effects associated with fatty acid transport. The term“enhancer” or “agonist”, as used herein, refers to an agent whichaugments, enhances, or increases fatty acid transport into the cytoplasmof a cell. An antagonist will decrease fatty acid concentration, fattyacid metabolism and byproduct levels in the cell, leading to phenotypicand molecular changes.

In order to produce a “host cell” type suitable for fatty acid uptakeassays and for assays derived therefrom for identifying inhibitors orenhancers thereof, a nucleic acid vector can be constructed to comprisea gene encoding a fatty acid transport protein, for example, humanFATP1, FATP2, FATP3, FATP4, FATP5, FATP6, a mutant or variant thereof,an ortholog of the human proteins, such as mouse orthologs or orthologsfound in other mammals, or a FATP family protein of origin in anorganism other than a mammal. The gene of the vector can be regulatable,such as by the placement of the gene under the control of an inducibleor repressible promoter in the vector (e.g., inducible or repressible bya change in growth conditions of the host cell harboring the vector,such as addition of inducer, binding or functional removal of repressorfrom the cell millieu, or change in temperature) such that expression ofthe FATP gene can be turned on or initiated by causing a change ingrowth conditions, thereby causing the protein encoded by the gene to beproduced, in host cells comprising the vector, as a plasma membraneprotein. Alternatively, the FATP gene can be constitutively expressed.

A vector comprising an FATP gene, such as a vector described herein, canbe introduced into host cells by a means appropriate to the vector andto the host cell type. For example, commonly used methods such aselectroporation, transfection, for instance, transfection using CaCl₂,and transduction (as for a virus or bacteriophage) can be used. Hostcells can be, for example, mammalian cells such as primary culture cellsor cells of cell lines such as COS cells, 293 cells or Jurkat cells.Host cells can also be, in some cases, cells derived from insects, cellsof insect cell lines, bacterial cells, such as E. coli, or yeast cells,such as S. cerevisiae. It is preferred that the fatty acid transportprotein whose function is to be assessed, with or without a candidateinhibitor or enhancer, be produced in host cells whose ancestor cellsoriginated in a species related to the species of origin of the FATPgene encoding the fatty acid transport protein. For example, it ispreferable that tests of function or of inhibition or enhancement of amammalian FATP be carried out in host mamnmalian cells producing theFATP, rather than bacterial cells or yeast cells.

Host cells comprising a vector comprising a regulatable FATP gene can betreated so as to allow expression of the FATP gene and production of theencoded protein (e.g., by contacting the cells with an inducer compoundthat effects transcription from an inducible promoter operably linked tothe FATP gene).

The test agent (e.g., an agonist or antagonist) is added to the cells tobe used in a fatty acid transport assay, in the presence or absence oftest agent, under conditions suitable for production and/or maintenanceof the expressed FATP in a conformation appropriate for association ofthe FATP with test agent and substrate. For example, conditions underwhich an agent is assessed, such as media and temperature requirements,can, initially, be similar to those necessary for transport of typicalfatty acid substrates across the plasma membrane. One of ordinary skillin the art will know how to vary experimental conditions depending uponthe biochemical nature of the test agent. The test agent can be added tothe cells in the presence of fatty acid, or in the absence of fatty acidsubstrate, with the fatty acid substrate being added following theaddition of the test agent. The concentration at which the test agentcan be evaluated can be varied, as appropriate, to test for an increasedeffect with increasing concentrations.

Test agents to be assessed for their effects on fatty acid transport canbe any chemical (element, molecule, compound), made synthetically, madeby recombinant techniques or isolated from a natural source. Forexample, test agents can be peptides, polypeptides, peptoids, sugars,hormones, or nucleic acid molecules, such as antisense nucleic acidmolecules. In addition, test agents can be small molecules or moleculesof greater complexity made by combinatorial chemistry, for example, andcompiled into libraries. These libraries can comprise, for example,alcohols, alkyl halides, amines, amides, esters, aldehydes, ethers andother classes of organic compounds. Test agents can also be natural orgenetically engineered products isolated from lysates of cells,bacterial, animal or plant, or can be the cell lysates themselves.Presentation of test compounds to the test system can be in either anisolated form or as mixtures of compounds, especially in initialscreening steps.

Thus, the invention relates to a method for identifying agents whichalter fatty acid transport, the method comprising providing the testagent to the cell (wherein “cell” includes the plural, and can includecells of a cell strain, cell line or culture of primary cells or organculture, for example), under conditions suitable for binding to itstarget, whether to the FATP itself or to another target on or in thecell, wherein the transformed cell comprises a FATP.

In greater detail, to test one or more agents or compounds (e.g., amixture of compounds can conveniently be screened initially) forinhibition of the transport function of a fatty acid transport protein,the agent(s) can be contacted with the cells. The cells can be contactedwith a labeled fatty acid. The fatty acid can be, for example, a knownsubstrate of the fatty acid transport protein such as oleate orpalmitate. The fatty acid can itself be labeled with a radioactiveisotope, (e.g., ³H or ¹⁴C) or can have a radioactively labeled adductattached. In other variations, the fatty acid can have chemicallyattached to it a fluorescent label, or a substrate for an enzymeoccurring within the cells, wherein the substrate yields a detectableproduct, such as a highly colored or fluorescent product. Addition ofcandidate inhibitors and labeled substrate to the cells comprising fattyacid transport protein can be in either order or can be simultaneous.

A second aliquot of cells, which can be called “control” cells (a“first” aliquot of cells can be called “test” cells), is treated, ifnecessary (as in the case of transformed “host” cells), so as to allowexpression of the FATP gene, and is contacted with the labeled substrateof the fatty acid transport protein. The second aliquot of cells is notcontacted with one or more agents to be tested for inhibition of thetransport function of the protein produced in the cells, but isotherwise kept under the same culture conditions as the first aliquot ofcells.

In a filrther step of a method to identify inhibitors of a fatty acidtransport protein, the labeled fatty acid is measured in the first andsecond aliquots of cells. A preliminary step of this measurement processcan be to separate the external medium from the cells so as to be ableto distinguish the labeled fatty acid external to the cells from thatwhich has been transported inside the cells. This can be accomplished,for instance, by removing the cells from their growth container,centrifuging the cell suspension, removing the supernatant andperforming one or more wash steps to extensively dilute the remainingmedium which may contain labeled fatty acid. Detection of the labeledfatty acid can be by a means appropriate to the label used. For example,for a radioactive label, detection can be by scintillation counting ofappropriately prepared samples of cells (e.g., lysates or proteinextracts); for a fluorescent label, by measuring fluorescence in thecells by appropriate instrumentation.

If a compound tested as a candidate inhibitor of transport functioncauses the test cells to have less labeled fatty acid detected in thecells than that detected in the control cells, then the compound is aninhibitor of the fatty acid transport protein. Procedures analogous tothose above can be devised for identifying enhancers (agonists of FATPs)of fatty acid transport function wherein if the test cells contain morelabeled fatty acid than that detected in the control cells, or if thefatty acid is taken up at a higher rate, then the compound being testedcan be concluded to be an enhancer of the fatty acid transport protein.

Example 13 describes use of an assay of this type to identify aninhibitor of a FATP. In Example 13, an antisense oligonucleotide whichspecifically inhibits biosynthesis of mmFATP4 was demonstrated toinhibit fatty acid uptake into mouse enterocytes. Similarly, antisenseoligonucleotides directed towards specifically inhibiting thebiosynthesis of FATP6 in heart cells, FATP5 in liver cells, FATP3 inlung cells, and FATP2 in colon cells, can be demonstrated as examples of“test agents” that inhibit fatty acid transport.

Another assay to determine whether an agent is an inhibitor (orenhancer) of fatty acid transport employs animals, one or more of whichare administered the agent, and one or more of which are maintainedunder similar conditions, but are not administered the agent. Bothgroups of animals are given fatty acids (e.g., orally, intravenously, bytube inserted into stomach or intestine), and the fatty acids taken upinto a bodily fluid (e.g., serum) or into an organ or tissue of interestare measured from comparable samples taken from each group of animals.The fatty acids may carry a label (e.g., radioactive) to facilitatedetection and quantitation of fatty acids taken up into the fluid ortissue being sampled. This type of assay can be used alone or can beused in addition to in vitro assays of a candidate inhibitor orenhancer.

An agent determined to be an inhibitor (or enhancer) of FATP function,such as fatty acid binding and/or fatty acid uptake, can be administeredto cells in culture, or in vivo, to a mammal (e.g. human) to inhibit (orenhance) FATP function. Such an agent may be one that acts directly onthe FATP (for example, by binding) or can act on an intermediate in abiosynthetic pathway to produce FATP, such as transcription of the FATPgene, processing of the mRNA, or translation of the mRNA. An example ofsuch an agent is antisense oligonucleotide.

Antisense methods similar to those illustrated in Example 13 can be usedto determine the target FATP of a compound or agent that has aninhibitory or enhancing effect on fatty acid uptake. For example,antisense oligonucleotide directed to the inhibition of FATP4biosynthesis can be added to lung cells or cell lines derived from lungcells. In addition, antisense oligonucleotides directed to theinhibition of other FATPs, except for FATP3, can also be added to thelung cells. The administration of antisense oligonucleotides in thismanner ensures that the predominant FATP activity remaining in the cellscomes from FATP3. After a period of incubation of the cells with theantisense oligonucleotides sufficient to deplete the plasma membrane ofthe FATPs whose biosynthesis has been inhibited, a test agent,preferably one that has been shown by some preliminary test to have aninhibitory or enhancing activity on fatty acid transport, can be addedto the lung cells. If the test agent is now demonstrated, aftertreatment of the cells with antisense oligonucleotides, to have aninhibitory or enhancing activity on fatty acid transport in the lungcells, it can be concluded that the target of the test agent is FATP3,or a molecule involved in the biosynthesis or activity of FATP3.

In another type of cell-based assay for uptake of fatty acids, a changeof intracellular pH resulting from the uptake of fatty acids can befollowed by an indicator fluorophore. The fluorophore can be taken up bythe cells in a preincubation step. Fatty acids can be added to the cellmedium, and after some period of incubation to allow FATP-mediateduptake of fatty acids, the change in λ_(max) of fluorescence can bemeasured, as an indicator of a change in intracellular pH, as theλ_(max) of fluorescence of the fluorophore changes with the pH of itsenvironment, thereby indicating uptake of fatty acids. One suchfluorophore is BCECF (2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein; Rink, T. J. et al., J.Cell. Biol. 95: 189 (1982)).

In assays similar to those described above, a candidate inhibitor orenhancer of fatty acid transport function can be added (or mock-added,for control cultures) to cultures of cells engineered to express adesired FATP to which fatty acid substrate is also added. Inhibition offatty acid uptake is indicated by a lack of the drop in pH, indicatingfatty acid uptake, that is seen in control cells. Enhancement of fattyacid uptake is indicated by a decrease in intracellular pH, as comparedto control cells not receiving the candidate enhancer of fatty acidtransport function.

Yeast cells can be used in a similar cell-based assay for the uptake offatty acids mediated by a FATP, and such an assay can be adapted to ascreening assay for the identification of agents that inhibit or enhancefatty acid uptake by an FATP. Yeast cells lacking an endogenous FATPactivity (mutated, disrupted or deleted for FAT1; Faergeman, N. J. etal., J. Biol. Chem. 272(13):8531-8538 (1997); Watkins, P. A. et al., J.Biol. Chem. 273(29):18210-18219 (1998)) can be engineered to harbor arelated gene of the family of FATP-encoding genes, such as a mammalianFATP (e.g., human FATP4).

Examples of expression vectors include pEG (Mitchell, D. A., et al.,Yeast 9:715-10 723 (1993)) and pDAD1 and pDAD2, which contain a GAL1promoter (Davis, L. I. and Fink, G. R., Cell 61:965-978 (1990)). Avariety of promoters are suitable for expression. Available yeastvectors offer a choice of promoters. In one embodiment, the inducibleGAL1 promoter is used. In another embodiment, the constitutive ADH1promoter (alcohol dehyrodrogenase; Bennetzen, J. L. and Hall, B. D., J.Biol. Chem. 257:3026-3031 (1982)) can be used to express an insertedgene on glucose-containing media. An example of a vector suitable forexpression of a heterologous FATP gene in yeast is pQB169.

With the introduced FATP gene providing the only fatty acid transportprotein function for the yeast cells, it is possible to study effect ofthe heterologous FATP on fatty acid transport into the yeast cells inisolation. Assays for the uptake of fatty acids into the yeast cells canbe devised that are similar to those described above and/or those assaysthat have been illustrated in the Examples. Tests for candidateinhibitors or enhancers of the heterologous FATP can be done in culturesof yeast cells, wherein the yeast cells are incubated with fatty acidsubstrate and an agent to be tested as an inhibitor or enhancer of FATPfunction. FATP uptake after a period of time can be measured byanalyzing the contents of the yeast cells for fatty acid substrate, ascompared with control yeast cells incubated with the fatty acid, but notwith the test agent. Yeast cells have the additional advantage, overmammalian cells in culture, for example, that yeast cells can be forcedto rely upon fatty acids as their only source of carbon, if the growthmedium supplied to the yeast cells is formulated to contain no othersource of carbon. Thus, the effect of the heterologous FATP on fattyacid uptake and metabolism in the engineered yeast cells can beamplified. An agent that efficiently blocks transport function of theheterologous FATP could result in death of the yeast cells. Thus, inthis case, inhibition of function of the heterologous FATP can result inloss of viability. A simple measure of viability is turbidity of theyeast suspension culture, which can be adapted to a high throughputscreening assay for effects of various agents to be tested, usingmicrotiter plates or similar devices for small-volume cultures of theengineered yeast cells.

Cell-free assays can also be used to measure the transport of fattyacids across a membrane, and therefor also to assess a test treatment ortest agent for its effect on the rate or extent of fatty acid transport.An isolated FATP, for example in the presence of a detergent thatpreserves the native 3-dimensional structure of the FATP, or partiallypurified FATP, can be used in an artificial membrane system typicallyused to preserve the native conformation and activity of membraneproteins. Such systems include liposomes, artificial bilayers ofphospholipids, isolated plasma membrane such as cell membrane fragments,cell membrane fractions, or cell membrane vesicles, and other systems inwhich the FATP can be properly oriented within the membrane to havetransport activity. Assays for transport activity can be performed usingmethods analogous to those that can be used in cells engineered topredominantly express one FATP whose function is to be measured. Alabeled (e.g., radioactively labeled) fatty acid substrate can beincubated with one side of a bilayer or in a suspension of liposomesconstructed to integrate a properly oriented FATP. The accumulation offatty acids with time can be measured, using appropriate means to detectthe label (e.g., scintillation counting of medium on each side of thebilayer, or of the contents of liposomes isolated from the surroundingmedium). Assays such as these can be adapted to use for the testing ofagents which might interact with the FATP to produce an inhibitory or anenhancing effect on the rate or extent of fatty acid transport. That is,the above-described assay can be done in the presence or absence of theagent to be tested, and the results compared.

For examples of isolation of membrane proteins (ADP/ATP carrier anduncoupling protein), reconstitution into phospholipid vesicles, andassays of transport, see Klingenberg, M. et al., Methods Enzymol.260:369-389 (1995). For an example of a membrane protein (phosphatecarrier of Saccharomyces cerevisiae) that was purified and solubilizedfrom E. coli inclusion bodies, see Schroer, A. et al., J. Biol. Chem.273: 14269-14276 (1998). The Glutl glucose transporter of rat has beenexpressed in yeast. A crude membrane fraction of the yeast was preparedand reconstituted with soybean phospholipids into liposomes. Glucosetransport activity could be measured in the liposomes (Kasahara, T. andKasahara, M., J. Biol. Chem. 273: 29113-29117 (1998)). Similar methodscan be applied to the proteins and polypeptides of the invention.

Another embodiment of the invention is a method for inhibiting fattyacid uptake in a mammal (e.g., a human), comprising administering to themammal a therapeutically effective amount of an inhibitor of thetransport function of one or more of the fatty acid transport proteins,thereby decreasing fatty acid uptake by cells comprising the fatty acidprotein(s). Where it is desirable to reduce the uptake of fatty acids,for example, in the treatment of chronic obesity or as a part of aprogram of weight control or hyperlipidemia control in a human, one ormore inhibitors of one or more of the fatty acid transport proteins canbe administered in an effective dose, and by an effective route, forexample, orally, or by an indwelling device that can deliver doses tothe small intestine. The inhibitor can be one identified by methodsdescribed herein, or can be one that is, for instance, structurallyrelated to an inhibitor identified by methods described herein (e.g.,having chemical adducts to better stabilize or solubilize theinhibitor). The invention further relates to compositions comprisinginhibitors of fatty acid uptake in a mammal, which may further comprisepharmaceutical carriers suitable for administration to a subject mammal,such as sterile solubilizing or emulsifying agents.

A further embodiment of the present invention is a method of enhancingor increasing fatty acid uptake, such as enhancing or increasing LCFAuptake in the small intestine (e.g., to treat or prevent a malabsorptionsyndrome or other wasting condition) or in the liver (e.g., by anenhancer of FATP5 transport activity to treat acute liver failure) or inthe kidney (e.g., by an enhancer of FATP2 transport activity to treatkidney failure). In this embodiment, a therapeutically effective amountof an enhancer of the transport function of one or more of the fattyacid transport proteins can be administered to a mammalian subject, withthe result that fatty acid uptake in the small intestine is enhanced. Inthis embodiment, one or more enhancers of one or more of fatty acidtransport proteins is administered in an effective dose and by a route(e.g., orally or by a device, such as an indwelling catheter or otherdevice) which can deliver doses to the gut. The enhancer of FATPfunction (e.g., an enhancer of FATP4 function) can be identified bymethods described herein or can be one that is structurally similar toan enhancer identified by methods described herein.

Aerobic reperfusion of ischemic myocardium is a common clinical eventwhich can occur during such treatments as cardiac surgery, angioplasty,and thrombolytic therapy after a myocardial infarction. Duringreperfusion, a rapid recovery of myocardial energy production isessential for the complete recovery of contracthe function. Not only theextent of recovery of myocardial energy metabolism but also the type ofenergy substrate used by the heart during reperfusion are importantdeterminants of functional recovery. Circulating fatty acid levelsincrease following acute myocardial infarction or during cardiacsurgery, such that during and following ischemia the heart muscle can beexposed to very high concentrations of fatty acids (Lopaschuk, G. D. andW. C. Stanley, Science and Medicine (November/December 1997)). Highplasma fatty acid concentrations increase the severity of ischemicdamage in a number of experimental models of cardiac ischemia and havebeen linked to depression of mechanical function during aerobicreperfusion of previously ischemic hearts. Further data show thatmodifying fatty acid utilization can be beneficial for heart function inischemia and can be a useful approach for the treatment of angina. See,e.g., Desideri and Celegon, Am. J. Cardiol. 82(5A):50K-53K; Lopaschuk,Am. J. Cardiol. 82(5A):14K-17K. Plasma fatty acid concentrations can bereduced by administering to a human subject or other mammal an effectiveamount of an inhibitor of a FATP such as FATP2 or FATP4, therebyproviding a way of reducing fatty acid utilization by the heart.

In a further embodiment of the invention, a therapeutically effectiveamount of an inhibitor of hsFATP6 can be administered to a human patientby a suitable route, to reduce the uptake of fatty acids by cardiacmuscle. This treatment is desirable in patients who are diagnosed ashaving, or who are at risk of, abnormal accumulations of fatty acids inthe heart or a detrimentally high rate of uptake of fatty acids into theheart, because of ischemic heart disease, or following ischemia ortrauma to the heart.

The invention further relates to antibodies that bind to an isolated orrecombinant fatty acid transport protein of the FATP family, includingportions of antibodies, which can specifically recognize and bind to oneor more FATPs. The antibodies and portions thereof of the inventioninclude those which bind to one or more FATPs of mouse or othermammalian species. In a preferred embodiment, the antibodiesspecifically bind to a naturally occurring FATP of humans. Theantibodies can be used in methods to detect or to purify a protein ofthe present invention or a portion thereof by various methods ofimmunoaffinity chromatography, to inhibit the function of a protein in amethod of therapy, or to selectively inactivate an active site, or tostudy other aspects of the structure of these proteins, for example.

The antibodies of the present invention can be polyclonal or monoclonal.The term antibody is intended to encompass both polyclonal andmonoclonal antibodies. Antibodies of the present invention can be raisedagainst an appropriate immunogen, including proteins or polypeptides ofthe present invention, such as an isolated or recombinant FATP1, FATP2,FATP3, FATP4, FATP5, FATP6, mtFATP, ceFATPa, ceFATPb, scFATP or portionsthereof, or synthetic molecules, such as synthetic peptides (e.g.,conjugated to a suitable carrier). Preferred embodiments are antibodiesthat bind to any of the following: hsFATP1, hsFATP2, hsFATP3, hsFATP4,hsFATP5 or hsFATP6. The immunogen can be a polypeptide comprising aportion of a FATP and having at least one function of a fatty acidtransport protein, as described herein.

The term antibody is also intended to encompass single chain antibodies,chimeric, humanized or primatized (CDR-grafted) antibodies and the like,as well as chimeric or CDR-grafted single chain antibodies, comprisingportions from more than one species. For example, the chimericantibodies can comprise portions of proteins derived from two differentspecies, joined together chemically by conventional techniques orprepared as a single contiguous protein using genetic engineeringtechniques (e.g., DNA encoding the protein portions of the chimericantibody can be expressed to produce a contiguous protein chain. See,e.g., Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., EuropeanPatent No. 0,125,023 B1; Boss et al., U.S. Pat. No. 4,816,397; Boss etal., European Patent No. 0,120,694 BI; Neuberger, M. S. et al., WO86/01533; Neuberger, M. S. et al., European Patent No. 0,194,276 B1;Winter, U.S. Pat. No. 5,225,539; Winter, European Patent No. 0,239,400B1; Queen et al., U.S. Pat. No. 5,585,089; and Queen et al., EuropeanPatent No. EP 0 451 216 B1. See also, Newman, R. et al., BioTechnology,10:1455-1460 (1992), regarding primatized antibody, and Ladner et al.,U.S. Pat. No. 4,946,778 and Bird, R. E. et al., Science, 242:423-426(1988) regarding single chain antibodies.)

Whole antibodies and biologically functional fragments thereof are alsoencompassed by the term antibody. Biologically functional antibodyfragments which can be used include those fragments sufficient forbinding of the antibody fragment to a FATP to occur, such as Fv, Fab,Fab′ and F(ab′)₂ fragments. Such fragments can be produced by enzymaticcleavage or by recombinant techniques. For instance, papain or pepsincleavage can generate Fab or F(ab′)₂ fragments, respectively. Antibodiescan also be produced in a variety of truncated forms using antibodygenes in which one or more stop codons have been introduced upstream ofthe natural stop site. For example, a chimeric gene encoding a F(ab′)₂heavy chain portion can be designed to include DNA sequences encodingthe CH, domain and hinge region of the heavy chain.

Preparation of immunizing antigen (whole cells comprising FATP on thecell surface or purified FATP), and polyclonal and monoclonal antibodyproduction can be performed using any suitable technique. A variety ofmethods have been described (See e.g., Kohler et al., Nature, 256:495-497 (1975) and Eur. J. Immunol. 6: 511-519 (1976); Milstein et al.,Nature 266: 550-552 (1977); Koprowski et al., U.S. Pat. No. 4,172,124;Harlow, E. and D. Lane, 1988, Antibodies: A Laboratory Manual, (ColdSpring Harbor Laboratory: Cold Spring Harbor, N.Y.); Chapter 11 InCurrent Protocols In Molecular Biology, Vol. 2 (containing supplementsup through Supplement 42, 1998), Ausubel, F. M. et al., eds., (JohnWiley & Sons: New York, N.Y.)). Generally, a hybridoma can be producedby fusing a suitable immortal cell line (e.g., a myeloma cell line suchas SP2/0) with antibody producing cells. The antibody producing cells,preferably those obtained from the spleen or lymph nodes, can beobtained from animals immunized with the antigen of interest.Immunization of animals can be by introduction of whole cells comprisingfatty acid transport protein on the cell surface. The fused cells(hybridomas) can be isolated using selective culture conditions, andcloned by limiting dilution. Cells which produce antibodies with thedesired specificity can be selected by a suitable assay (e.g., ELISA).

Other suitable methods of producing or isolating antibodies (includinghuman antibodies) of the requisite specificity can used, including, forexample, methods which select recombinant antibody from a library (e.g.,Hoogenboom et al., WO 93/06213; Hoogenboom et al., U.S. Pat. No.5,565,332; WO 94/13804, published June 23, 1994; and Dower, W. J. etal., U.S. Pat. No. 5,427,908), or which rely upon immunization oftransgenic animals (e.g., mice) capable of producing a full repertoireof human antibodies (see e.g., Jakobovits et al., Proc. Natl. Acad. Sci.USA, 90: 2551-2555 (1993); Jakobovits et al., Nature, 362:255-258(1993); Lonberg et al., U.S. Pat. No. 5,569,825; Lonberg et al., U.S.Pat. No. 5,545,806; Surani et al., U.S. Pat. No. 5,545,807; andKucherlapati, R. et al., European Patent No. EP 0 463 151 B1).

Another aspect of the invention is a method for directing an agent tocardiac muscle. The differential expression of FATP6 in cardiac musclebut not in other tissue types allows for the specific targeting ofdrugs, diagnostic agents, tagging labels, histological stains or othersubstances specifically to cardiac muscle. A targeting vehicle can beused for the delivery of such a substance. Targeting vehicles which bindspecifically to FATP6 can be linked to a substance to be delivered tothe cells of cardiac muscle. The linkage can be, for instance, via oneor more covalent bonds, or by high affinity non-covalent bonds. Atargeting vehicle can be an antibody, for instance, or other compound(e.g., a fatty acid or fatty acid analog) which binds to FATP6 with highspecificity.

Targeting vehicles specific to the heart-specific protein FATP6 have invivo (e.g., therapeutic and diagnostic) applications. For example, anantibody which specifically binds to FATP6 can be conjugated to a drugto be targeted to the heart (e.g., a cardiac glycoside to treatcongestive heart failure, or β-adrenergic agents, sodium channelblockers or calcium channel blockers to treat arrhythmias). A substance(e.g., a radioactive substance) which can be detected (e.g., a label) invivo can also be linked to a targeting vehicle which specifically bindsto a heart-specific protein such as FATP6, and the conjugate can be usedas a labeling agent to identify cardiac muscle cells.

Targeting vehicles specific to FATP6 find further applications in vitro.For example, an FATP6-specific targeting vehicle, such as an antibody (apolyclonal preparation or monoclonal) which specifically binds to FATP6,can be linked to a substance which can be used as a stain for a tissuesample (e.g., horseradish peroxidase) to provide a method for theidentification of cardiac muscle in a sample, as can be used inembryology studies, for example.

In a similar manner, an agent can be directed to the liver of a mammal,as FATP5 is expressed in liver but not in other tissue types. Atargeting vehicle which specifically binds to FATP5 can be conjugated toa drug for delivery of the drug to the liver, such as a drug to treathepatitis, Wilson's disease, lipid storage diseases and liver cancer. Aswith targeting vehicles specific to FATP6, targeting vehicles specificto FATP5 can be used in studying tissue samples in vitro.

The invention also relates to compositions comprising a modulator ofFATP function. The term “modulate” as used herein refers to the abilityof a molecule to alter the function of another molecule. Thus, modulatecould mean, for example, inhibit, antagonize, agonize, upregulate,downregulate, induce, or suppress. A modulator has the capability ofaltering function of its target. Such alteration can be accomplished atany stage of the transcription, translation, expression or function ofthe protein, so that, for example, modulation of a target gene can beaccomplished by modulation of the DNA or RNA encoding the protein, andthe protein itself.

Antagonists or agonists (inhibitors or enhancers) of the FATPs of theinvention, antibodies that bind a FATP, or mimetics of a FATP can beemployed in combination with a non-sterile or sterile carrier orcarriers for use with cells, tissues or organisms, such as apharmaceutical carrier suitable for administration to a mammaliansubject. Such compositions comprise, for instance, a media additive or atherapeutically effective amount of an inhibitor or enhancer compound tobe identified by an assay of the invention and a pharmaceuticallyacceptable carrier or excipient. Such carriers may include, but are notlimited to, saline, buffered saline, dextrose, water, ethanol,surfactants, such as glycerol, excipients such as lactose andcombinations thereof. The formulation can be chosen by one of ordinaryskill in the art to suit the mode of administration. The chosen route ofadministration will be influenced by the predominant tissue or organlocation of the FATP whose function is to be inhibited or enhanced. Forexample, for affecting the function of FATP4, a preferred administrationcan be oral or through a tube inserted into the stomach (e.g., directstomach tube or nasopharyngeal tube), or through other means toaccomplish delivery to the small intestine. The invention furtherrelates to diagnostic and pharmaceutical packs and kits comprising oneor more containers filled with one or more of the ingredients of theaforementioned compositions of the invention.

Compounds of the invention which are FATPs, FATP fusion proteins, FATPmimetics, FATP gene-specific antisense poly- or oligonucleotides,inhibitors or enhancers of a FATP may be employed alone or inconjunction with other compounds, such as therapeutic compounds. Thepharmaceutical compositions may be administered in any effective,convenient manner, including administration by topical, oral, anal,vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous,intranasal, transdermal or intradermal routes, among others. In therapyor as a prophylactic, the active agent may be administered to anindividual as an injectable composition, for example as a sterileaqueous dispersion, preferably isotonic.

Alternatively, the composition may be formulated for topicalapplication, for example, in the form of ointments, creams, lotions, eyeointments, eye drops, ear drops, mouthwash, impregnated dressings andsutures and aerosols, and may contain appropriate conventionaladditives, including, for example, preservatives, solvents to assistdrug penetration, and emollients in ointments and creams. Such topicalformulations may also contain compatible conventional carriers, forexample cream or ointment bases, and ethanol or oleyl alcohol forlotions.

In addition, the amount of the compound will vary depending on the size,age, body weight, general health, sex, and diet of the host, and thetime of administration, the biological half-life of the compound, andthe particular characteristics and symptoms of the disorder to betreated. Adjustment and manipulation of established dose ranges are wellwithin the ability of those of skill in the art.

A further aspect of the invention is a method to identify apolymorphism, or the presence of an alternative or variant allele of agene in the genome of an organism (of interest here, genes encodingFATPs). As used herein, polymorphism refers to the occurrence of two ormore genetically determined alternative sequences or alleles in apopulation. A polymorphic locus may be as small as a base pair.Polymorphic markers include restriction fragment length polymorphisms,variable number of tandem repeats (VNTR's), hypervariable regions,minisatellites, dinucleotide repeats, trinucleotide repeats,tetranucleotide repeats, simple sequence repeats, and insertion elementssuch as Alu. The first identified alleleic form, or the most frequentlyoccurring form can be arbitrarily designated as the reference (usually,“wildtype”) form, and other allelic forms are designated as alternative(sometimes, “mutant” or “variant”). Dipolid organisms may be homozygousor heterozygous for allelic forms.

An “allele” or “allelic sequence” is an alternative form of a gene whichmay result from at least one mutation in the nucleotide sequence.Alleles may result in altered mRNAs or polypeptides whose structure orfunction may or may not be altered. Any given gene may have none, one,or many allelic forms (polymorphism). Common mutational changes whichgive rise to alleles are generally ascribed to natural deletions,additions, or substitutions of nucleotides. Each of these types ofchanges may occur alone, or in combination with the others, one or moretimes in a given sequence.

Several different types of polymorphisms have been reported. Arestriction fragment length polymorphism (RFLP) is a variation in DNAsequence that alters the length of a restriction fragment (Botstein etal., Am. J. Hum. Genet. 32:314-331 (1980)). The restriction fragmentlength polymorphism may create or delete a restriction site, thuschanging the length of the restriction fragment. RFLPs have been widelyused in human and animal genetic analyses (see WO 90/13668; WO 90/11369;Donis-Keller, Cell 51:319-337 (1987); Lander et al., Genetics 121:85-99(1989)). When a heritable trait can be linked to a particular RFLP, thepresence of the RFLP in an individual can be used to predict thelikelihood that the individual will also exhibit the trait.

Other polymorphisms take the form of short tandem repeats (STRs) thatinclude tandem di-, tri- and tetra-nucleotide repeated motifs. Thesetandem repeats are also referred to as variable number tandem repeat(VNTR) polymorphisms. VNTRs have been used in identity and paternityanalysis (U.S. Pat. No. 5,075,217; Armour et al., FEBS Lett. 307:113-115(1992); Hornet al., WO 91/14003; Jeffreys, EP 370,719), and in a largenumber of genetic mapping studies.

Other polymorphisms take the form of single nucleotide variationsbetween individuals of the same species. Such polymorphisms are far morefrequent than RFLPs, STRs (short tandem repeats) and VNTRs (variablenumber tandem repeats). Some single nucleotide polymorphisms occur inprotein-coding sequences, in which case, one of the polymorphic formsmay give rise to the expression of a defective or other variant proteinand, potentially, a genetic disease. Other single nucleotidepolymorphisms occur in noncoding regions. Some of these polymorphismsmay also result in defective protein expression (e.g., as a result ofdefective splicing). Other single nucleotide polymorphisms have nophenotypic effects.

Many of the methods described below require amplification of DNA fromtarget samples and purification of the amplified products. This can beaccomplished by PCR, for instance. See generally, PCR Technology,Principles and Applications for DNA Amplification (ed. H. A. Erlich),Freeman Press, New York, N.Y., 1992; PCR Protocols: A Guide to Methodsand Applications (eds. Innis, et al.), Academic Press, San Diego,Calif., 1990; Mattila et al., Nucleic Acids Res. 19:4967 (1991); Eckertet al., PCR Methods and Applications 1:17 (1991); PCR (eds. McPherson etal., IRS Press, Oxford); and U.S. Pat. No. 4,683,202.

Other suitable amplification methods include the ligase chain reaction(LCR) (see Wu and Wallace, Genomics 4:560 (1989); Landegren et al.,Science 241:1077 (1988)), transcription amplification (Kwoh et al.,Proc. Natl. Acad. Sci. USA 86:1173 (1989), self-sustained sequencereplication (Guatelli et al., Proc. Natl. Acad. Sci. USA 87:1874 (1990),and nucleic acid based sequence amplification (NASBA). The latter twoamplification methods involve isothermal reactions based on isothermaltranscription, which produce both single stranded RNA (ssRNA) and doublestranded DNA (dsDNA) as the amplification products in a ratio of about30 or 100 to 1, respectively.

Another aspect of the invention is a method for detecting a variantallele of a human FATP gene, comprising preparing amplified, purifiedFATP DNA from a reference human and amplified, purified, FATP DNA from a“test” human to be compared to the reference as having a variant allele,using the same or comparable amplification procedures, and determiningwhether the reference DNA and test DNA differ in DNA sequence in theFATP gene, whether in a coding or a noncoding region, wherein, if thetest DNA differs in sequence from the reference DNA, the test DNAcomprises a variant allele of a human FATP gene. The following is adiscussion of some of the methods by which it can be determined whetherthe reference FATP DNA and test FATP DNA differ in sequence.

Direct Sequencing. The direct analysis of the sequence of variantalleles of the present invention can be accomplished using either thedideoxy chain termination method or the Maxam and Gilbert method (seeSambrook et al., Molecular Cloning: A Laboratory Manual, 2nd ed., ColdSpring Harbor Press, N.Y. 1989; Zyskind et al., Recombinant DNALaboratory Manual, Acad. Press, 1988)).

Denaturing Gradient Gel Electrophoresis. Amplification productsgenerated using the polymerase chain reaction can be analyzed by the useof denaturing gradient gel eletrophoresis. Different alleles can beidentified based on the different sequence-dependent strand dissociationproperties and electrophoretic migration of DNA in solution (chapter 7in Erlich, ed. PCR Technology, Principles and Applications for DNAAmplification, W. H. Freeman and Co., New York, 1992).

Single-strand Conformation Polymorphism Analysis. Alleles of targetsequences can be differentiated using single-strand conformationpolymorphism analysis, which identifies base differences by alterationin electrophoretic migration of single stranded PCR products, asdescribed in Orita et al., Proc. Natl. Acad. Sci. USA 86:2766-2770(1989). Amplified PCR products can be generated as described above, andheated or otherwise denatured, to form single-stranded amplificationproducts. Single-stranded nucleic acids may refold or form secondarystructures which are partially dependent on the base sequence. Thedifferent electrophoretic mobilities of single-stranded amplificationproducts can be related to base-sequence differences between alleles oftarget sequences.

Detection of Binding by Protein That Binds to Mismatches. Amplified DNAcomprising the FATP gene or portion of the gene of interest from genomicDNA, for example, of a normal individual is prepared, using primersdesigned on the basis of the DNA sequences provided herein. AmplifiedDNA is also prepared, in a similar manner, from genomic DNA of anindividual to be tested for bearing a distinguishable allele. Theprimers used in PCR carry different labels, for example, primer 1 withbiotin, and primer 2 with ³²P. Unused primers are separated form the PCRproducts, and the products are quantitated. The heteroduplexes are usedin a mismatch detection assay using immobilized mismatch binding protein(MutS) bound to nitrocellulose. The presence of biotin-labeled DNAwherein mismatched regions are bound to the nitrocellulose via MutSprotein, is detected by visualizing the binding of streptavidin tobiotin. See WO 95/12689. MutS protein has also been used in thedetection of point mutations in a gel-mobility-shift assay (Lishanski,A. et al., Proc. Natl. Acad. Sci. USA 91:2674-2678 (1994)).

Other methods, such as those described below, can be used to distinguisha FATP allele from a reference allele, once a particular allele has beencharacterized as to DNA sequence.

Allele-specific probes. The design and use of allele-specific probes foranalyzing polymorphims is described by e.g., Saiki et al., Nature324:163-166 (1986); Dattagupta, EP 235,726, Saiki, WO 89/11548.Allele-specific probes can be designed so that they hybridize to asegment of a target DNA from one individual but do not hybridize to thecorresponding segment from another individual due to the presence ofdifferent polymorphic forms in the respective segments from the twoindividuals. Hybridization conditions should be sufficiently stringentthat there is a significant difference in hybridization intensitybetween alleles, and preferably an essentially binary response, wherebya probe hybridizes to only one of the alleles. Some probes are designedto hybridize to a segment of target DNA such that the polymorphic sitealigns with a central position (e.g., in a 15-mer at the 7 position; ina 16-mer, at either the 8 or 9 position) of the probe. This design ofprobe achieves good discrimination in hybridization between differentallelic forms.

Allele-specific probes are often used in pairs, one member of a pairshowing a perfect match to a reference form of a target sequence and theother member showing a perfect match to a variant form. Several pairs ofprobes can then be immobilized on the same support for simultaneousanalysis of multiple polymorphisms within the same target sequence.

Allele-specific Primers. An allele-specific primer hybridizes to a siteon target DNA overlapping a polymorphism, and only primes amplificationof an allelic form to which the primer exhibits perfect complementarity.See Gibbs, Nucleic Acid Res. 17:2427-2448 (1989). This primer is used inconjunction with a second primer which hybridizes at a distal site.Amplification proceeds from the two primers, resulting in a detectableproduct which indicates the particular allelic form is present. Acontrol is usually performed with a second pair of primers, one of whichshows a single base mismatch at the polymorphic site and the other ofwhich exhibits perfect complementarity to a distal site. The single-basemismatch prevents amplification and no detectable product is formed. Themethod works best when the mismatch is included in the 3′-most positionof the oligonucleotide aligned with the polymorphism because thisposition is most destabilizing to elongation from the primer (see, e.g.,WO 93/22456).

Gene Chips. Allelic variants can also be identified by hybridization tonucleic acids immobilized on solid supports (gene chips), as described,for example, in WO 95/11995 and U.S. Pat. No. 5,143,854, both of whichare incorporated herein by reference. WO 95/11995 describes subarraysthat are optimized for detection of a characterized variant allele. Sucha subarray contains probes designed to be complementary to a secondreference sequence, which is an allelic variant of the first referencesequence.

The present method is illustrated by the following examples, which arenot intended to be limiting in any way.

EXAMPLES

Materials and Methods

The following Materials and Methods were used in the work described inExamples 1-5.

Sequence Alignment of FATP Clones. The DNA sequence for mouse FATP1 wasobtained from the National Center for Biotechnology Informationnonredundant database. cDNAs for mmFATP2, 3, 4, and 5 were obtained byscreening mouse expression libraries (purchased from GIBCO/BRL) withprobes derived from the cloned expressed sequence tags (ESTs) (ResearchGenetics, Huntsville, AL). Full-length clones were obtained for mmFATP2and 5 and partial sequences for mmFATP3 and 4. The sequences describedherein have been deposited in the GenBank database (Accession Nos.FATP2, AF072760; FATP3, AP072759; FATP4, AF072758; FATP5, AF072757).

Neither FATP2 nor FATP5 contains an in-frame stop codon upstream of theputative initiator methionine; initiator methionines were assigned byhomology with that in mmFATP1 and by the presence of a signal sequenceimmediately after it. The Mycobacterium tuberculosis, Caenorhabditiselegans, and Saccharomyces cerevisiae sequences were present in thedbEST database as part of the sequencing projects for these organisms.Sequences were aligned utilizing a ClustalX algorithm and the resultingalignment exported to SeqVu. Homologous amino acid substitutions areboxed in FIG. 1 and were determined using the Dayhoff 250 method with a50% homology cutoff.

Cell Transfection and LCFA Uptake. COS cells were cotransfected usingthe DEAE-dextran method with the mammalian expression vector pCDNA 3.1(Invitrogen) expressing the gene for CD2 (pCDNA-CD2) in combination witheither a pCDNA 3.1 or pCMVSPORT2 (GIBCO/BRL) expression vectorcontaining one of the murine or nematode FA TP genes (PCDNA-mmFATP1,pCDNA-FA TP2, pCMVSPORT-FA TP5, pCDNA-ceFATPb). Two days aftertransfection, cells were assayed for CD2 expression with aphycoerythrin-coupled anti-CD2(PE-CD2) monoclonal antibody (PharMingen),and fatty acid uptake was assayed with a BODIPY-labeled fatty acidanalogue (Molecular Probes). Briefly, cells were washed twice with PBS(phosphate buffered saline) and stained with PE-CD2 at 4° C. for 30 minin PBS containing 10% fetal calf serum. They were then washed threetimes with PBS/fetal calf serum for 5 min followed by an incubation for2 min at 37° C. in fatty acid uptake solution, which contained 0.1 μMBODIPY-FA and 0.1% fatty acid-free BSA (bovine serum albumin) in PBS(Schaffer, J. E. & Lodish, H. F. (1994) Cell 79:427-436). After 2 min,the cells were washed four times with ice-cold PBS/0.1% BSA. The cellswere then removed from the plates with PBS containing 5 mM EDTA andresuspended in PBS containing 10% fetal calf serum and 10 mM EDTA.PE-CD2 and BODIPY-FA fluorescence were measured using a FACScan (BectonDickinson). COS cells were gated on forward scatter (FSC) and sidescatter (SS). Cells exhibiting more than 300 CD2 fluorescence units(dsim) representing 15% of all cells were deemed CD2 positive and theirBODIPY-FA fluorescence was quantitated.

E. coli-Based LCFA Uptake Assay. The full-length coding region of mtFATPand a control protein, the mammalian transcription factor TFE3, weresubcloned into the inducible, prokaryotic expression vector pET(Novagen). Expression was induced with 1 mM isopropylβ-D-thiogalactoside (IPTG) for 1 hour, or cells were left uninduced.Cells were washed in PBS/0.1% BSA and resuspended in 1 ml PBS/0.1% BSAcontaining 0.1 μM [³H]palmitate (NEN) at 37° C. Uptake was stopped afterthe indicated incubation time by transferring the cells onto filterpaper using a cell harvester (Brandel, Bethesda, MD). Filters werewashed extensively with ice-cold PBS/0.1% BSA, and [³H]palmitate wasquantitated by scintillation counting.

Northern Blots. Northern blot analysis of murine FATP expression wasdone using poly(A) mRNA blots (Clontech). Probes of each of the FATPswere derived from the 3′ untranslated regions of each gene and were <60%identical in sequence. Probes were labeled by random priming (BoehringerMannheim) and hybridized at 65° C. Blots were extensively washed in 0.2%SSC/0.1% SDS at 65° C.

Generation of Phylogenetic Trees. Complete and partial sequences forFATP genes from human, rat, mouse, puffer fish, Drosophila melanogaster,C. elegans, S. cerevisiae, and M. tuberculosis were aligned usingClustalX. A homologous region of 48 amino acids (residues 472-519 inmmFATP1) from all of the genes was used to determine phylogeneticrelationship within ClustalX. Based on these data a phylogenetic treewas generated using Tree View PPC (FIG. 5).

Nomenclature. It is proposed that the FATP genes be given a speciesspecific prefix (mm, Mus musculus; hs, Homo sapiens; mt, M.tuberculosis; dm, D. melanogaster; ce, C. elegans, sc, S. cerevisiae)and numbered such that mammalian homologues in different species sharethe same number but differ in their prefix. Since the two C. elegansgenes cannot be paired with a specific human or mouse FATP, they havebeen designated ceFATPa and ceFATPb.

Example 1 Identification of Novel Mammalian FATPs

The National Center for Biotechnology Information EST database wasscreened, using the mouse FATP protein sequence (mmFATP1), to identifynovel FATPs. This strategy led to the identification of more than 50murine EST sequences which could be assembled into five distinctcontiguous DNA sequences (contigs). One contig was identical to thepreviously cloned FATP, which has been renamed FATP1. Another, which hasbeen renamed FATP2, is the murine homologue of a rat gene previouslyidentified by others as a very long chain acyl-CoA synthase (Uchiyama,A., Aoyama, T., Kamijo, K., Uchida, Y., Kondo, N., Orii, T. & Hashimoto,T. (1996) J. Biol. Chem. 271:30360-30365). The other three contigsrepresented novel genes (FATP3, 4, and 5). Full-length clones for FATP2and FATP5 and nearly complete sequences for FATP3 and 4 (FIG. 1) wereobtained by screening cDNA libraries made from mouse day 10.5 embryosand adult liver. Also identified were human homologues for each of themurine genes in the EST database. A sixth human gene was alsoidentified; whether this gene is also present in the mouse will requireadditional studies. Map positions are given in Tables 2 and 3.

The genetic loci for all of the human genes, with the exception of FATP5which was already mapped as an unknown EST, were determined using theradiation hybrid panels. The map positions given below show the distance(in centiRays) from the closest framework marker. As a guideline, thereare approximately 300 kb/cR.

TABLE 2 Mapping Data for Human Genes hsFATP1 Chromosome Chr19 places13.35 cR from WI-6344 (lod > 3.0) hsFATP2 Chromosome Chr15 places 4.92cR from D15S126 (lod > 3.0) hsFATP3 Chromosome Chrl places 13.24 cR fromWI-2862 (lod > 3.0) hsFATP4 Chromosome Chr9 places 7.80 cR from WI-9685(lod > 3.0) hsFATP5 unknown EST previously mapped to near D19S418hsFATP6 Chromosome Chr5 places 1.41 cR from WI-4907 (lod > 3.0)

The mouse map is an internal backcross panel consisting of 188 mousebackcross DNA's plus 4 controls (B6, Spretus, F1, Water). The backcrosswas constructed by crossing B6 by Spretus animals and then crossingthose F1's back to B6. Mapping is accomplished by taking advantage ofrecombinational events during meiosis, and the use of PCR primers todetect the differences (by size or re-annealing events) at any givenlocus between the B6 and Spretus allele.

For the purposes of mapping, a novel set of primers (gene of interest)is used to amplify from all 188 DNA's and then typed as being a B6 (“B”)or a Spretus (“S”). This string of B's and S's is entered into the MapManager program, which does a best fit calculation by comparing thestring of 188 typings from the gene of interest to all loci alreadyextant in the panel, for all 20 chromosomes. The gene of interest isthen assigned to a particular area on a particular chromosome accordingto a number of parameters, including the minimalization of doublecross-overs, and the highest LOD scores. Indicated in Table 3 aredistances to the closest markers on either side of the FATP locus.

TABLE 3 Mapping Data for Mouse Genes mmFATP1 Chromosome 8 places 2.82 cMfrom D8Mit132 (lod 43.4) and 1.81 cM from D8Mit74 (lod 43.5) mmFATP2Chromosome 2 places 1.29 cM from D2Mit258 (lod 47.9) and 1.75 cM fromD2NDS3 (lod 44.9) mmFATP3 Chromosome 3 places 2.54 cM from D3Mit22 (lod29.5) and 19.62 cM from D3Mit42 (lod 13.6) mmFATP4 Chromosome 2 places13.78 cM from D2Mit1 (lod 22.9) and 3.85 cM from D2Mit65 (lod 41.9)mmFATP5 Chromosome 7 places 7.28 cM proximal of D7Mit21 (lod 28.3)

Example 2 Assessment of Function

The ability of the newly identified mouse genes to function as fattyacid transporters was assessed using a fluorescence-activated cellsorting-based assay. COS cells were transiently cotransfected withexpression vectors encoding the cell surface protein CD2 and eithermmFATP1, mmFATP2, or mmFATP5, respectively. Two days after transfection,COS cells were stained with an antibody to CD2 and then incubated with aBODIPY-labeled fatty acid [BODIPY-FA, (Schaffer, J. E. & Lodish, H. F.(1994) Cell 79:427-436)]. The cells were then washed extensively, liftedoff the dish, and analyzed by fluorescence-activated cell sorting. Asjudged by the number of CD2-positive cells, the transfection efficiencywas approximately 20-30%. Fatty acid uptake was quantitated in thetransiently transfected COS cells by measuring the BODIPY-FAfluorescence of the CD2-positive cells. Expression of CD2 had no effecton fatty acid uptake as shown by the finding that COS cells expressingonly the transfected CD2 cDNA (CD2-positive) had the same low level ofBODIPY-FA uptake as did untransfected (CD2-negative) control cells (FIG.2A, control). In COS cells cotransfected with CD2 and mmFATP1, mmFATP2,or mmFATP5, uptake of BODIPY-FA by the transfected (CD2-positive) cellswas increased between 15- to 90-fold over control (CD2 cDNA only) cells(FIGS. 2A-2D).

Example 3 Expression Patterns of Murine FATPs

Expression patterns of members of the murine FATP gene family werecharacterized by Northern blot analysis; to avoid cross-hybridization,the probes used were from the 3′ untranslated region of these genes,which are less than 60% identical in sequence. The expression pattern ofFATP1 agrees with that previously found (Schaffer, J. E. & Lodish, H. F.(1994) Cell 79:427-436). Here, expression was seen primarily in heartand kidney. FATP2 is expressed almost exclusively in liver and kidney,which corresponds to the reported tissue distribution of the rathomologue [very long chain acyl-CoA (VLACS)] as assessed by Westernblotting (Uchiyama, A., Aoyama, T., Kamijo, K., Uchida, Y., Kondo, N.,Orii, T. & Hashimoto, T. (1996) J. Biol. Chem. 271:30360-30365). FATP3is present in lung, liver, and testis. FATP5 is expressed only in liverand cannot be detected in other tissues even when the blot isoverexposed. The human homologue of FATP5 is also liver specific and isnot expressed in a wide array of other tissues tested, including fetalliver.

Example 4 FATPs Are Evolutionarily Conserved

The EST database was searched, using sequences conserved among the fivemurine FATP genes, for FATP genes in other organisms. Two homologueswere found in C. elegans and one in M. tuberculosis. One of the C.elegans genes was cloned from a cDNA library and expressed in COS cells,as described for the murine FATPs. Overexpression of the nematode FATPresulted in a 15-fold increase of BODIPY-FA uptake compared with controlcells (FIG. 3). The mycobacterial FATP gene was isolated from a phagelibrary and assessed for its ability to facilitate fatty acid uptake. E.coli transformed with a prokaryotic, isopropylβ-D-thiogalactoside-inducible expression vector containing themycobacterial FATP gene demonstrated a significant increase in the rateof [³H]palmitate uptake after induction, compared with uninducedbacteria or E. coli transformed with a control protein (FIG. 4). NovelFATP genes were also identified in F. rubripes (puffer fish) and D.melanogaster.

Example 5 Phylogenetic Tree of FATPs

Faergeman et al. (Faergeman, N. J., DiRusso. C. C., Elberger, A.,Knudsen, J. & Black, P. N. (1997) J. Biol. Chem. 272:8531-8538)identified three regions of very strong conservation between the scFATPand mmFATP1 genes. The sequences of the FATPS were compared over a 311-amino acid FATP “signature sequence” which includes these conservedregions corresponding to amino acids 246-557 in mmFATP1 (underlined inFIG. 1). When compared with the National Center for BiotechnologyInformation nonredundant database, only one region of the “FATPsignature sequence” shows significant homology to other proteins. Thissmall stretch of amino acids (underlined in FIG. 1) is an AMP-bindingmotif found in a multitude of other proteins, such as acyl-CoA synthase,several CoA lipases, and gramicidin S synthetase component II (Schaffer,J. E. & Lodish, H. F. (1994) Cell 79:427-436). The relevance of thismotif to fatty acid transport is unclear. Other highly conserved regionsamong the FATPs, including long stretches of amino acids >90% identicalfrom mycobacteria to humans, are not found in any other class ofproteins. A 48-amino acid segment of the FATP signature sequence wasused to construct a phylogenetic tree (FIG. 5). Each of the human andmouse genes form their own branch; hsFATP6, which as yet has no murinehomologue, is most closely related to hsFATP3 and mmFATP3. As expected,rnVLACS is closer in sequence to mmFATP2 than to hsFATP2. The FATP genesof invertebrates i.e., C. elegans and D. melanogaster, are most closelyrelated to each other. Surprisingly, the mycobacteral gene is moreclosely related to the human and mouse FATP5 genes than to the FATPs ofany of the lower organisms. Whether this reflects coevolution of themycobacterial and human genes awaits further study.

Materials and Methods

The following materials and methods were used in the work described in

Examples 6-10

Isolation of fill-length human FATP 1 and 4

Full-length clones encoding human FATP1 and human FATP4 were identifiedby searching databases for sequences similar to murine FATP1-5 codingregions using the BlastX algorithm (Altschul et al., J. Mol. Biol. 215:403-410, 1990).

A concatamer of nucleotide sequences comprising the coding sequences ofmmFATP1 (Genbank Accession U15976), mmFATP2, mmFATP3 (SEQ ID NO:6),mmFATP4 (SEQ ID NO:8) and mmFATP5 (SEQ ID NO:10) was used to search theMillennium database using the BLASTX algorithm. Sequences with ascore >150 were evaluated for whether they represented known FATP codingsequences.

Human clones with similarity to the 5′ end of murine FATP sequences weresequenced completely. Clones encoding full-length human FATP1 wereobtained from a heart cDNA library constructed in the mammalianexpression vector pMET7 (Tartaglia et al., Cell, 83: 1263-1271, 1995).Clones encoding full-length human FATP4 were obtained from a spleen CDNAlibrary constructed in the mammalian expression vector pMET7.

Isolation of full-length human FATP6

Several clones encoding human FATP6 were identified by searching publicdatabases as described above. Five clones were analyzed further byrestriction digestion and DNA sequencing. One of these clones (GenbankAccession # AA412064) appeared to be full-length and its entire insertwas sequenced.

DNA Sequence Analysis

Sequences were aligned with the DNAStar program using the Clustalmethod. Hydrophobicity plots were generated with DNA Strider using theKyte Doolittle method.

In situ hybridization

Tissues were collected from 8 week old C57/B16 mice. Tissues were freshfrozen, cut on a cryostat at 10 μm thickness and mounted on SuperfrostPlus slides (VWR). Sections were air dried for 20 minutes and thenincubated with ice cold 4% paraformaldehyde (PFA)/phosphate bufferedsaline (PBS) for 10 minutes. Slides were washed 2 times 5 minutes withPBS, incubated with 0.25% acetic anhydride/1 M triethanolamine for 10minutes, washed with PBS for 5 minutes and dehydrated with 70%, 80%, 95%and 100% ethanol for 1 minute each. Sections were incubated withchloroform for 5 minutes. Hybridizations were performed with³⁵S-radiolabeled (5×10⁷ cpm/ml) cRNA probes generated from the 3′untranslated regions of mouse FATPs by PCR followed by in vitrotranscription in the presence of 50% formamide, 10% dextran sulfate,1×Denhardt's solution, 600 mM NaCl, 10 mM DTT, 0.25% SDS and 10 μg/mltRNA for 18 hours at 55° C. After hybridization, slides were washed with10 mM Tris-HCl pH 7.6, 500 mM NaCl, 1 mM EDTA (TNE) for 10 minutes,incubated in 40 μg/ml RNase A in TNE at 37° C. for 30 minutes, washed inTNE for 10 minutes, incubated once in 2×SSC at 60° C. for 1 hour, oncein 0.2×SSC at 60° C. for 1 hour, once in 0.2×SSC at 65° C. for 1 hourand dehydrated with 50%, 70%, 80%, 90% and 100% ethanol. Localization ofmRNA transcripts was detected by dipping slides in Kodak NBT-2photoemulsion and exposing for 7 days at 4° C., followed by developmentwith Kodak Dektol developer. Slides were counter stained withhaematoxylon and eosin and photographed. Controls for the in situhybridization experiments include the use of a sense probe which showedno signal above background in all cases.

Northern Blotting

Human mRNA blots were obtained from Invitrogen or Clontech. PCRfragments from the 3′ untranslated regions of human FATPs were used asprobes. Blots were probed with ³²P-labeled DNA probes using theRapid-Hyb buffer (Amersham) according to the manufacturer'sinstructions.

Cell transfection and LCFA uptake. COS cells were cotransfected, usinglipofectamine (GIBCO BRL) according to the manufacturer's instructions,with the mammalian expression vector pCDNA3.1 (Invitrogen) expressingthe gene for CD2 in combination with a pMET7 expression vector(Tartaglia et al., Cell, 83:1263 -1271, 1995) containing hsFATP1(pMET7-hsFATP1) or hsFATP4 (pMET7-hsFATP4) or pMET7 alone. Two daysafter transfection, cells were assayed for CD2 expression with aphycoerythrin-coupled anti-CD2 (PE-CD2) monoclonal antibody(PharMingen), and fatty acid uptake was assayed with a BODIPY-labeledfatty acid analog (Molecular Probes) as described above.

Example 6 Determination of Expression of mmFATPs

mmFATP4, and to lesser extent mmFATP2, are expressed at high levels inthe brush border layer of the small intestine.

Cell transfection and LCFA uptake. COS cells were cotransfected, usinglipofectamine (GIBCO BRL) according to the manufacturer's instructions,with the mammalian expression vector pCDNA3.1 (Invitrogen) expressingthe gene for CD2 in combination with a pMET7 expression vector(Tartaglia et al., Cell, 83:1263-1271, 1995) containing hsFATP1(pMET7-hsFATP1) or hsFATP4 (pMET7-hsFATP4) or pMET7 alone. Two daysafter transfection, cells were assayed for CD2 expression with aphycoerythrin-coupled anti-CD2 (PE-CD2) monoclonal antibody(PharMingen), and fatty acid uptake was assayed with a BODIPY-labeledfatty acid analog (Molecular Probes) as described above.

Absorption of dietary fat requires transport of free fatty acids acrossthe apical membrane of epithelial cells in the small intestine. Previousstudies suggested that this transport is protein-mediated; however, thetransport protein had not yet been identified. In situ hybridization wasperformed on each of the three regions of the small intestine—duodenum,jejunum and ileum—as well as the colon, using probes from the 3′untranslated regions of mm-FATP1, mmFATP2, mmFATP3, mmFATP4 and mmFATP5,to determine whether any of the mouse FATPs are expressed in the smallintestine. It was expected that a protein involved in fatty acidabsorption would be expressed in the epithelial cells of the smallintestine, but absent from the colon.

Expression of mmFATPs in the jejunum was identical to that in the ileumin all cases. High levels of mmFATP4 mRNA were present in the epithelialcells of the jejunum and ileum, and lower, but significant, amounts weredetected in the epithelial cells of the duodenum. Significantly, FATP4mRNA was absent from other cell types of the small intestine and noFATP4 mRNA could be detected in any of the cells of the colon. FATP2mRNA was present in the epithelial cells of the duodenum at a levelsimilar to that of FATP4, but was present at lower levels in the jejunumand ileum. No signals above background were detected for mmFATP1,mmFATP3 and mmFATP5 in any of the intestinal tissues. mmFATP3 and FATP5were clearly detectable by in situ hybridization in adult liver andmmFATP 1 could be detected in a variety of tissues on a whole embryo insitu, indicating that the FATP1, 3, and 5 probes were working.

mmFATP4 expression is predominant in the small intestine compared to theother organs of the mouse embryo. In the small intestine, FATP4expression is limited to differentiated enterocytes, while no signal isdetected in the connective tissue or the undifferentiated epithelialcells in the crypts. Differentiated enterocytes are known to be thecells that mediate the uptake of fatty acids. FATP4 is specifically andstrongly expressed in the epithelial cells of adult murine duodenum andileum but not colon. Other FATPs, such as FATP5, are not expressed inthe small intestine. Thus, FATP4 is the major FATP in the mouse smallintestine. Given its high level of expression, it is likely that FATP4,and to a lesser extent FATP2, play an important role in the absorptionof fatty acids.

mmFATP2, and mmFATP5 are expressed in hepatocytes

Northern analysis of mmFATP2, mmFATP3, mmFATP4 and mmFATP5 showedexpression in the liver. To determine whether these proteins are presentin hepatocytes or other cells types present in liver homogenates, insitu hybridizations were performed. mmFATP2, and mmFATP5 mRNA wasclearly present in hepatocytes, and was not concentrated in other celltypes such as endothelial cells or macrophages. No signal abovebackground was detected for mmFATP1 in any of the cell types in theliver, consistent with the results of the Northern blotting.

Example 7 Isolation and Sequence Analysis of Full-length Human FATP1 andFull-length Human FATP4

To identify human cDNA clones encoding FATP family members, Millenniumdatabases were searched for sequences similar to murine FATP 1-5 codingregions. Two clones were analyzed in detail; inspection of the entireDNA sequence of these two clones showed that they encode the humanorthologs of mmFATP1 and mmFATP4, respectively. These two clones weredesignated hsFATP1 and hsFATP4, and their DNA and predicted proteinsequences are shown in FIGS. 44A-44C and 45, and 50A-50C and 51. hsFATP1is predicted to encode a 646 amino acid, 71 kD protein with multiplemembrane-spanning domains (FIG. 28A). HsFATP4 is predicted to encode a643 amino acid, 72 kD protein with multiple membrane spanning domains(See FIG. 29A). A comparison of the DNA sequences of mouse and humanFATP1 and mouse and human FATP4 (FIGS. 30A-30B and 31A-31B) shows thatthe mouse and human orthologs are 85% (FATP1) and 87% (FATP4) identicalto each other within the coding sequences given in these figures. At theamino acid level, hsFATP1 and hsFATP4 are ˜90% identical to theirrespective mouse orthologs within the coding region shown in thesefigures (FIGS. 32 and 33). The sequence identities between mouse andhuman FATP1 and FATP4 are considerably higher than the ones observedbetween different FATP family members within one species (˜40%-60%) andare present in the N-terminal part of the protein, a region that ispoorly conserved between different FATP family members. This high degreeof sequence conservation clearly demonstrates that the newly identifiedhuman FATPs are orthologs of mouse FATP1 and FATP4 rather than novelFATP family members.

Table 4 is an identity/similarity matrix comparing the amino acidsequences of FATP1 and 4 from human and mouse. This shows that the genewhose sequence is shown in FIG. 43A is indeed human FATP4, since it is91% identical with the murine FATP4 but only 62% identical with theclosest related human FATP, which is FATP 1.

TABLE 4 Identity/Similarity Matrix hsFATP4 mmFATP4 hsFATP1 mmFATP1hsFATP4 — 93.2 72.3 72.0 mmFATP4 91.0 — 71.2 71.1 hsFATP1 61.9 61.0 —92.4 mmFATP1 60.7 59.6 89.5 —

Example 8 Isolation and Sequence Analysis of Full-length Human FATP6

A search of EST databases identified a set of overlapping humansequences that were similar to FATPs, but did not have a clear mouseortholog. One of these EST clones was found to encode a full-lengthcDNA. The entire insert of this clone was sequenced and designatedhsFATP6. The DNA and predicted protein sequences of hsFATP6 are shown inFIGS. 54A-54C and 55. HsFATP6 is predicted to encode a 619 amino acid,70 kD protein with multiple membrane-spanning domains (FIG. 35A). Acomparison of the amino acid sequences of hsFATP6 with other human FATPsshows about 37% identity to either hsFATP1 or hsFATP4 (FIG. 36). Thisdegree of sequence identity is similar to what is observed betweendifferent mouse FATPs. The phylogenetic analysis described above clearlydemonstrates that hsFATP6 is a member of the FATP family, but not anortholog of any of the mouse FATPs. Comparisons were done with “ALIGN”(E. Myers and W. Miller, “Optimal Alignments in Linear Space,” CABIOS4:11-17 (1988) using standard settings.

Example 9 Tissue Distribution of Human FATPs

The tissue distribution of human FATPs was assessed by Northernblotting. Human FATP3 was expressed in a large variety of tissues. Incontrast, human FATP5 was present at high levels in the liver, but wasundetectable in all other tissues examined. Thus, both hsFATP3 andhsFATP5 recapitulate the expression pattern of their mouse orthologs(see above). HsFATP6 is a novel FATP with no mouse ortholog as yet.Northern blotting shows that hsFATP6 is expressed at high levels in theheart, but is undetectable in other tissues, including skeletal andsmooth muscle. This tissue distribution suggests that human FATP6performs an important role in energy metabolism in the heart; blockingFATP6-mediated fatty acid transport may therefore be beneficial for anumber of heart diseases, e.g., ischemic heart disease.

To identify the major FATP expressed in the human small intestine,Northern blotting was performed on a blot containing mRNA from humanstomach, jejunum, ileum, colon, rectum and lung. hsFATP5 and hsFATP6were undetectable in any of these tissues. FATP5 is only expressed inliver and FATP6 only in heart. hsFATP2 was weakly expressed in thecolon, and an even weaker signal was detectable in jejunum, ileum andlung lanes. hsFATP3 was expressed well in the lung, but was only weaklyexpressed in the other tissues tested. Importantly, no difference wasseen in the expression of hsFATP3 between small intestine and stomach orcolon, suggesting that the expression observed is not related to fattyacid absorption in the small intestine. hsFATP4 was clearly expressed inboth jejunum and ileum; expression was significantly lower in the colonand was absent in the stomach. This expression pattern is consistentwith a major role for FATP4 in absorption of fatty acids in the humangut.

Example 10 Expression of hsFATP1 and hsFATP4 Promotes Transport of FattyAcids

COS cells were cotransfected using lipofectamine with the mammalianexpression vector pCDNA-CD2 in combination with one of theFATP-containing expression vectors (pMET7-hsFATP1 or pMET7-hsFATP4) oran insertless expression vector (pMET7, control) as described inMaterials and Methods for Examples 6-10. COS cells were gated on forwardscatter and side scatter. Cells exhibiting more than 400 CD2fluorescence units representing ˜30% of all cells were deemedCD2-positive. The percent of CD2-positive cells exhibiting aBODIPY-fluorescence of >300 is plotted for the three different vectorstested (FIG. 37).

Example 11 Stable Expression of Human FATP4 in 293 Cells

Stable cell lines were generated as follows. A DNA fragment containingthe entire hsFATP4 coding sequence as well as 100 nucleotides of 5′ and50 nucleotides of 3′ untranslated region was inserted into the vectorpIRES-neo (Clontech) using standard cloning techniques. The resultingconstruct or a vector control (pIRES-neo) was transfected into 293 cellsusing the lipofectamine method (Gibco BRL) according to themanufacturer's directions. Cells that had taken up the DNA were selectedwith 1 mg/ml G418 (Gibco BRL). Single colonies were picked 1 to 2 weeksafter transfection and grown in medium containing 0.8 mg/ml G418.Colonies were screened for the ability to take up fatty acids bymeasuring uptake of a fluorescently labeled fatty acid (BODIPY-FA).About 40 colonies transfected with the pIRES-neo containing FATP4 and˜20 colonies transfected with pIRES-neo control were analyzed. All 20 ofthe vector control clones showed amounts of BODIFY-FA uptake similar toeach other and to untransfected 293 cells. In contrast, among the 40FATP4 transfected clones, 3 had a 5- to 10-fold increased BODIPY-FAuptake compared to any of the vector controls, and a large number (˜20)showed an approximately two-fold increase in BODIPY-FA levels. Thisdistribution is consistent with FATP4 conferring increased fatty aciduptake in these cells. One of the cell lines with the highest amount ofBODIPY-FA uptake was selected to be used for measuring uptake oftritiated fatty acid.

The uptake of tritiated oleate over time by either FATP4 expressing orcontrol cells was assayed over time. Expression of FATP4 increases therate of fatty acid uptake by over 3-fold, demonstrating that FATP4 is,like the other FATPs, a functional fatty acid transporter (FIG. 38).

Example 12 Immuno-staining with FATP4-Specific Antiserum

A polyclonal antiserum against the C-terminus of mmFATP4 was raisedusing a GST-fusion protein having mmFATP4-specific amino acid sequence552-643 (AVASP . . . GEEKL). In western blot experiments, the purifiedantibody reacted strongly with a synthetic peptide matching theC-terminus of mmFATP4, but not with a corresponding region of mmFATP2,mmFATP3, or mmFATP5. The mmFATP4 specific polyclonal antiserum detects,in western blot experiments with enterocyte lysates from 3 differentmice, a ˜70 kDa protein, which is in accordance with mmFATP4's predictedmolecular weight of 72 kDa. The binding is specific for mmFATP4, sinceit can be completely abolished by preincubation of the antiserum withthe GST-fusion peptide used to raise the antibody.

Immunofluorescence experiments were performed using the anti-mmFATP4antiserum on fresh frozen sections of murine small intestine. Theantibody binding demonstrates strong expression of mmFATP4 inenterocytes, confirming the results of the in situ hybridizationexperiments. At higher magnifications it is apparent that mmFATP4 isexpressed at the apical side of the enterocyte, indicating that thetransporter is present in the brush border membrane, which is known tomediate the uptake of fatty acids from the intestinal lumen.

Immuno-electron microscopy studies were performed on fresh frozen murineintestinal cells. The gold particles used, appearing as black specks onthe electron micrographs, indicate the subcellular localization ofmmFATP4 to be on the microvilli of the enterocyte. It can be seen fromthe electron micrographs that mmFATP4 is localized exclusively inmembranes, preferentially the apical plasma membrane, confirming that itis indeed a membrane protein.

Example 13 Inhibition of Fatty Acid Uptake Specific to FATP4Demonstrated in Isolated Mouse Enterocytes

Phosphorothioate derivatives of the following oligonucleotides weresynthesized:

FATP4-AS2 CCCCCACCAGAGAGGCTCC (SEQ ID NO:103) FATP4-AS2MMCCACCCCCGGAAAGCCTGC (SEQ ID NO:104) FATP4-S2 GGAGCCTCTCTGGTGGGGG (SEQ IDNO:105)

FATP4 AS2 is the antisense oligo; it is designed to be complementary tothe sequence extending from nucleotide 10 to nucleotide 28 of the mouseFATP4 coding sequence. FATP4-AS2MM is a control oligo; in the oligoevery third nucleotide was changed creating mismatches; the overallnucleotide composition is identical to FATP4-AS2 (same number of G, A,T, C). FATP4-S2 is the sense control.

Enterocytes were isolated from the small intestine of mice and incubatedfor 48 h in tissue culture (FIG. 40) either without oligonucleotides(squares) or with 100 μM FATP4 specific sense (circles) or antisense(diamonds) oligonucleotides. The uptake over time of 25 μM oleate wasthen measured. While the FATP4 sense oligonucleotide did notsignificantly influence the uptake, the antisense oligonucleotideinhibited fatty acid uptake by ˜50%.

The effect of either FATP4 sense, antisense or mismatch sequenceoligonucleotides on the uptake of fatty acids was measured inenterocytes. Isolated enterocytes were incubated with increasingconcentrations of FATP4 antisense oligonucleotides (solid bars in FIG.41), or a mismatch control oligonucleotide with identical nucleotidecomposition (stippled bars), or with 100 μM of the FATP4sense-oligonucleotide (lined bar). The medium for this incubation wasDulbecco's modified Eagle's medium with 4.5 g/L glucose, 1 mM sodiumpyruvate, 0.01 mg/ml human transferrin and 10% fetal bovine serum. After48 hours of incubation the uptake of oleate by enterocytes was measuredover a 5 minute time interval. Measurements were done in quadruplicate.The uptake assay was done in Hank's buffered salt solution with 10 mMtaurocholate. Only the enterocytes given FATP4 antisense oligonucleotideshowed a concentration dependent decrease of fatty acid uptake,inhibiting it at a 100 μM concentration by ˜50%. This effect was FATP4specific, since only the antisense oligonucleotide which can bind to theFATP4 mRNA and block its translation inhibited uptake, but not a controloligonucleotide differing only in the sequence but not the nucleotidecontent, ruling out a toxic or otherwise nonspecific inhibitory effectof this oligonucleotide due to its chemical composition.

As a further control experiment, the uptake of oleate was measured alongwith the uptake of methionine in the same cultured enterocytes.Antisense oligonucleotide, mismatch sequence oligonucleotide, or nooligonucleotide was added to a concentration of 100 μM to cultures ofenterocytes. After incubation for 48 hours, the uptake of both³H-labeled oleate and ³⁵S-labeled methionine was assayed. Results areshown in FIG. 42. Fatty acid uptake is at the left side of the pairedbars; methionine uptake is on the right side of the paired bars. Thefact that amino acid uptake was not influenced by the antisenseoligonucleotide treatment further supports the conclusion that theantisense oligonucleotide causes a specific reduction in translation ofFATP4-specific mRNA.

Example 14 mmFATP2 Is Expressed in Proximal Renal Tubule Epithelium

Northern analysis showed that mmFATP1, mmFATP2, and mmFATP4 are presentin the kidney. In situ hybridization (methods as for Example 6) wasperformed to determine which cell type(s) of the kidney these mRNAs areexpressed in. mmFATP1 IMRNA was present in virtually all cellsthroughout the kidney with no obvious preference for a particular celltype. In contrast, mmFATP2 was expressed only in the renal cortex.Within the cortex, expression of mmFATP2 was restricted to theepithelial cells of the proximal renal tubules. The primary function ofproximal renal tubule cells is the reabsorption of filtered salts andnutrients (e.g., glucose), a process that requires mitochondrialoxidation and that can utilize fatty acids as energy substrates. Basedon the localization of mmFATP2, it is possible that mmFATP2 is importantfor reabsorption in the kidney by allowing uptake of an energy source(fatty acids) from the blood into renal epithelial cells. Alternatively,if fatty acids need to be reabsorbed in the kidney, similarly toglucose, FATP2 could be involved in the reabsorption of fatty acids.Determination of the subcellular localization of FATP2 will distinguishbetween these two possibilities.

Table 5 summarizes data on expression of the mouse FATPs in variousorgans.

TABLE 5 Mouse FATP mRNA Expression Mouse Probes mFATP1 mFATP2 mFATP3mFATP4 mFATP5 E18.5 embryo everywhere, liver — Brain, Mouse expressionbrain = (hepatocytes) small intestine, Probes thymus > superior heart >brown cervical fat, others ganglion (SCG), dorsal root ganglion (DRG),other regions have lower expression Duodenum — villi (surface — villi(surface — epitheium) epithelium) Jejunum — villi (surface — villi(surface — epithelium) epithelium) Ileum — villi (surface — villi(surface — epithelium) epithelium) Colon low expression very low level —— — in the crypt in the crypt Kidney cortex and proximal — — — medullatubules Liver — hepatocytes hepatocytes — hepatocytes Pancreas exocrineexocrine — — — secretory units secretory units or acinar cells; oracinar cells; endocrine endocrine pancreas (islet) pancreas (islet) arenegative are negative Brain Neuronal — — Neuronal — expressionexpression throughout the throughout the brain including brain includinghypothalanius hypothalamus Heart myocytes — — Testis seminiferous —seminiferous tubules tubules Lung bronchiole — — Adipose adipocyteadipocyte —

Example 15 Isolation of full-length human FATP3

Full-length clones encoding human FATP3 were identified by searchingdatabases for sequences similar to the murine FATP1-5 coding regionsusing the BlastX algorithm (Altschul et al., J. Mol. Biol. 215: 403-410,1990). Human clones with similarity to the 5′ end of murine FATPsequences were sequenced completely. A clone encoding full-length humanFATP3 was obtained from a human bone library constructed in themammalian expression vector pMET7 (Tartaglia, L. A. et al., Cell 83:1263-1271, 1995). To identify human cDNA clones encoding FATP familymembers, databases were searched for sequences similar to murine FATP1-5coding regions. One clone was found to encode the human ortholog ofmmFATP3 and was designated hsFATP3. The DNA and predicted proteinsequences of hsFATP3 are shown in FIGS. 94A and 94B. hsFATP5 ispredicted to encode a 703 amino acid 75.6 kD protein with multiplemembrane-spanning domains. A comparison of the DNA sequences of mouseand human FATP3 shows that the mouse and human orthologs are 81%identical to each other within the coding region. At the amino acidlevel, hsFATP3 is ˜86% identical to mm FATP3 within the coding region.The sequence identities between mouse and human FATP3 are considerablyhigher than those observed between different FATP family members withinone species (˜40%) and are present in the N-terminal part of theprotein, a region that is poorly conserved between different FATP familymembers.

All references cited herein are incorporated by reference in theirentirety.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims.

105 1 340 PRT Mus musculus 1 Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu ProLys Pro Ala Ile Leu 1 5 10 15 Ser His Glu Arg Val Ile Gln Val Ser AsnVal Leu Ser Phe Cys Gly 20 25 30 Cys Arg Ala Asp Asp Val Val Tyr Asp ValLeu Pro Leu Tyr His Thr 35 40 45 Ile Gly Leu Val Leu Gly Phe Leu Gly CysLeu Gln Val Gly Ala Thr 50 55 60 Cys Val Leu Ala Pro Lys Phe Ser Ala SerArg Phe Trp Ala Glu Cys 65 70 75 80 Arg Gln His Gly Val Thr Val Ile GlnTyr Ile Gly Glu Ile Cys Arg 85 90 95 Tyr Leu Leu Arg Gln Pro Val Arg AspVal Glu Gln Arg His Arg Val 100 105 110 Arg Leu Ala Val Gly Asn Gly LeuArg Pro Ala Ile Trp Glu Glu Phe 115 120 125 Thr Gln Arg Phe Gly Val ProGln Ile Gly Glu Phe Tyr Gly Ala Thr 130 135 140 Glu Cys Asn Cys Ser IleAla Asn Met Asp Gly Lys Val Gly Ser Cys 145 150 155 160 Gly Phe Asn SerArg Ile Leu Thr His Val Tyr Pro Ile Arg Leu Val 165 170 175 Lys Val AsnGlu Asp Thr Met Glu Pro Leu Arg Asp Ser Glu Gly Leu 180 185 190 Cys IlePro Cys Gln Pro Gly Glu Pro Gly Leu Leu Val Gly Gln Ile 195 200 205 AsnGln Gln Asp Pro Leu Arg Arg Phe Asp Gly Tyr Val Ser Asp Ser 210 215 220Ala Thr Asn Lys Lys Ile Ala His Ser Val Phe Arg Lys Gly Asp Ser 225 230235 240 Ala Tyr Leu Ser Gly Asp Val Leu Val Met Asp Glu Leu Gly Tyr Met245 250 255 Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe Arg Trp Arg Gly GluAsn 260 265 270 Val Ser Thr Thr Glu Val Glu Ala Val Leu Ser Arg Leu LeuGly Gln 275 280 285 Thr Asp Val Ala Val Tyr Gly Val Ala Val Pro Gly ValGlu Gly Lys 290 295 300 Ala Gly Met Ala Ala Ile Ala Asp Pro His Ser GlnLeu Asp Pro Asn 305 310 315 320 Ser Met Tyr Gln Glu Leu Gln Lys Val LeuAla Ser Tyr Ala Arg Pro 325 330 335 Ile Phe Leu Arg 340 2 339 PRT Musmusculus 2 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Asn Pro Lys Pro Ala ValIle 1 5 10 15 Lys His Phe Arg Tyr Phe Trp Ile Ala Met Gly Ala Gly LysAla Phe 20 25 30 Gly Ile Asn Lys Ser Asp Val Val Tyr Ile Thr Met Pro MetTyr His 35 40 45 Ser Ala Ala Gly Ile Met Gly Ile Gly Ser Leu Ile Ala PheGly Ser 50 55 60 Thr Ala Val Ile Arg Lys Lys Phe Ser Ala Ser Asn Phe TrpLys Asp 65 70 75 80 Cys Val Lys Tyr Asn Val Thr Ala Thr Leu Tyr Val GlyGlu Ile Leu 85 90 95 Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro Glu Asp LysIle His Thr 100 105 110 Val Arg Leu Ala Met Gly Thr Gly Leu Arg Ala AsnVal Trp Lys Asn 115 120 125 Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile TrpGlu Phe Tyr Gly Ser 130 135 140 Thr Glu Gly Asn Val Gly Leu Met Asn TyrVal Gly His Cys Gly Ala 145 150 155 160 Val Gly Arg Thr Ser Cys Ile LeuArg Met Leu Thr Pro Phe Glu Leu 165 170 175 Val Gln Phe Asp Ile Glu ThrAla Glu Pro Leu Arg Asp Lys Gln Gly 180 185 190 Phe Cys Ile Pro Val GluPro Gly Lys Pro Gly Leu Leu Leu Thr Lys 195 200 205 Val Arg Lys Asn GlnPro Phe Leu Gly Tyr Arg Gly Ser Gln Ala Glu 210 215 220 Ser Asn Arg LysLeu Val Ala Asn Val Arg Arg Val Gly Asp Leu Tyr 225 230 235 240 Phe AsnThr Gly Asp Val Leu Thr Leu Asp Gln Glu Gly Phe Phe Tyr 245 250 255 PheGln Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val 260 265 270Ser Thr Gly Glu Val Glu Cys Val Leu Ser Ser Leu Asp Phe Leu Glu 275 280285 Glu Val Asn Val Tyr Gly Val Pro Val Pro Gly Cys Glu Gly Lys Val 290295 300 Gly Met Ala Ala Val Lys Leu Ala Pro Gly Lys Thr Phe Asp Gly Lys305 310 315 320 Lys Tyr Gln His Val Arg Ser Trp Leu Pro Ala Tyr Ala ThrPro His 325 330 335 Phe Ile Arg 3 345 PRT Caenorhabditis elegans 3 IleTyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser 1 5 10 15Trp Arg Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val Leu His 20 25 30Met Thr Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu Phe His Ser 35 40 45Thr Ala Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser His Gly Gly Cys 50 55 60Leu Ala Leu Ser His Lys Phe Ser Ala Ser Thr Phe Trp Lys Gln Val 65 70 7580 Tyr Leu Thr Gly Ala Thr His Ile Gln Tyr Ile Gly Glu Ile Cys Arg 85 9095 Tyr Leu Leu Ala Ala Asn Pro Cys Pro Glu Glu Lys Gln His Asn Val 100105 110 Arg Leu Met Trp Gly Asn Gly Leu Arg Gly Gln Ile Trp Lys Glu Phe115 120 125 Val Gly Arg Phe Gly Ile Lys Lys Ile Gly Glu Leu Tyr Gly SerThr 130 135 140 Glu Gly Asn Ser Asn Ile Val Asn Val Asp Asn His Val GlyAla Cys 145 150 155 160 Gly Phe Met Pro Ile Tyr Pro His Ile Gly Ser LeuTyr Pro Val Arg 165 170 175 Leu Ile Lys Val Asp Arg Ala Thr Gly Glu LeuGlu Arg Asp Lys Asn 180 185 190 Gly Leu Cys Val Pro Cys Val Pro Gly GluThr Gly Glu Met Val Gly 195 200 205 Val Ile Lys Glu Lys Asp Ile Leu LeuLys Phe Glu Gly Tyr Val Ser 210 215 220 Glu Gly Asp Thr Ala Lys Lys IleTyr Arg Asp Val Phe Lys His Gly 225 230 235 240 Asp Lys Val Phe Ala SerGly Asp Ile Leu His Trp Asp Asp Leu Gly 245 250 255 Tyr Leu Tyr Phe ValAsp Arg Cys Gly Asp Thr Phe Arg Trp Lys Gly 260 265 270 Glu Asn Val SerThr Thr Glu Val Glu Gly Ile Leu Gln Pro Val Met 275 280 285 Asp Val GluAsp Ala Thr Val Tyr Gly Val Thr Val Gly Lys Met Glu 290 295 300 Gly ArgAla Gly Met Ala Gly Ile Val Val Lys Asp Gly Thr Asp Val 305 310 315 320Glu Lys Phe Ile Ala Asp Ile Thr Ser Arg Leu Thr Glu Asn Leu Ala 325 330335 Ser Tyr Ala Ile Pro Val Phe Ile Arg 340 345 4 356 PRT Saccharomycescerevisiae 4 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala IleVal 1 5 10 15 Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe Gly His HisSer Tyr 20 25 30 Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys Leu Pro LeuTyr His 35 40 45 Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys Val Ile TyrGly Leu 50 55 60 Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser Arg Phe TrpAsp Asp 65 70 75 80 Cys Val Lys Tyr Asn Cys Thr Val Val Gln Tyr Val GlyGlu Val Cys 85 90 95 Arg Tyr Leu Leu His Thr Pro Ile Ser Lys Tyr Glu LysMet His Lys 100 105 110 Val Lys Val Ala Tyr Gly Asn Gly Leu Arg Pro AspIle Trp Gln Asp 115 120 125 Phe Arg Lys Arg Phe Asn Ile Glu Val Ile GlyGlu Phe Tyr Ala Ala 130 135 140 Thr Glu Ala Pro Phe Ala Thr Thr Thr PheGln Lys Gly Asp Phe Gly 145 150 155 160 Ile Gly Ala Cys Arg Asn Tyr GlyThr Ile Ile Gln Trp Phe Leu Ser 165 170 175 Phe Gln Gln Thr Leu Val ArgMet Asp Pro Asn Asp Asp Ser Val Ile 180 185 190 Tyr Arg Asn Ser Lys GlyPhe Cys Glu Val Ala Pro Val Gly Glu Pro 195 200 205 Gly Glu Met Leu MetArg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser 210 215 220 Phe Gln Gly TyrLeu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val 225 230 235 240 Arg AspVal Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu 245 250 255 LeuLys Ala Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly 260 265 270Asp Thr Phe Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val Glu 275 280285 Asp Gln Leu Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val Leu Val 290295 300 Val Gly Ile Lys Val Pro Lys Tyr Glu Gly Arg Ala Gly Phe Ala Val305 310 315 320 Ile Lys Leu Thr Asp Asn Ser Leu Asp Ile Thr Ala Lys ThrLys Leu 325 330 335 Leu Asn Asp Ser Leu Ser Arg Leu Asn Leu Pro Ser TyrAla Met Pro 340 345 350 Leu Phe Val Lys 355 5 334 PRT Mycobacteriumtuberculosis 5 Tyr Ile Phe Thr Ser Gly Thr Thr Gly Phe Pro Lys Ala SerVal Met 1 5 10 15 Thr His His Arg Trp Leu Arg Ala Leu Ala Val Phe GlyGly Met Gly 20 25 30 Leu Arg Leu Lys Gly Ser Asp Thr Leu Tyr Ser Cys LeuPro Leu Tyr 35 40 45 His Asn Asn Ala Leu Thr Val Ala Val Ser Ser Val IleAsn Ser Gly 50 55 60 Ala Thr Leu Ala Leu Gly Lys Ser Phe Ser Ala Ser ArgPhe Trp Asp 65 70 75 80 Glu Val Ile Ala Asn Arg Ala Thr Ala Phe Val TyrIle Gly Glu Ile 85 90 95 Cys Arg Tyr Leu Leu Asn Gln Pro Ala Lys Pro ThrAsp Arg Ala His 100 105 110 Gln Val Arg Val Ile Cys Gly Asn Gly Leu ArgPro Glu Ile Trp Asp 115 120 125 Glu Phe Thr Thr Arg Phe Gly Val Ala ArgVal Cys Glu Phe Tyr Ala 130 135 140 Ala Ser Glu Gly Asn Ser Ala Phe IleAsn Ile Phe Asn Val Pro Arg 145 150 155 160 Thr Ala Gly Val Ser Pro MetPro Leu Ala Phe Val Glu Tyr Asp Leu 165 170 175 Asp Thr Gly Asp Pro LeuArg Asp Ala Ser Gly Arg Val Arg Arg Val 180 185 190 Pro Asp Gly Glu ProGly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln 195 200 205 Pro Phe Asp GlyTyr Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val 210 215 220 Arg Asn AlaPhe Arg Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val 225 230 235 240 MetSer Pro Gln Gly Met Gly His Ala Ala Phe Val Asp Arg Leu Gly 245 250 255Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu 260 265270 Ala Ala Leu Ala Ser Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly 275280 285 Val Gln Ile Pro Arg Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr290 295 300 Leu Arg Ala Gly Ala Glu Phe Asp Gly Gln Ala Leu Ala Arg ThrVal 305 310 315 320 Tyr Gly His Leu Pro Gly Tyr Ala Leu Pro Leu Phe ValArg 325 330 6 2087 DNA Mus musculus 6 acgactcact atagggagag agctatgacgtcgcatgcac gcgtaagctt gggcccctcg 60 agggatcctc tagagcggcc gccgaccccgaaagctctga gagcgggtgc agtctggcct 120 ggcgtctcgc gtacctggcc cgggagcagccgacacacac cttcctcatc cacggcgcgc 180 agcgctttag ctacgcggag gctgagcgcgagagcaaccg gattgctcgc gcctttctgc 240 gcgcacgggg ctggaccggg ggccgccgaggctcgggcag gggcagcact gaggaaggcg 300 cacgcgtggc gcctccggct ggagatgcggctgctagagg gacgaccgcg ccccctctgg 360 cacccggggc gaccgtggcg ctgctcctcccagcgggccc ggatttcctt tggatttggt 420 tcggactggc caaagctggc ctgcgcacggcctttgtgcc caccgcttta cgccgaggac 480 ccctgctgca ctgcctccgc agctgcggtgcgagtgcgct cgtgctggcc acagagttcc 540 tggagtccct ggagccggac ctgccggccttgagagccat ggggctccac ctatgggcga 600 cgggccctga aactaatgta gctggaatcagcaatttgct atcggaagca gcagaccaag 660 tggatgagcc agtgccgggg tacctctctgccccccagaa cataatggac acctgcctgt 720 acatcttcac ctctggcact actggcctgcccaaggctgc tcgaatcagt catctgaagg 780 ttctacagtg ccagggattc taccatctgtgtggagtcca ccaggaggac gtgatctacc 840 tcgcactccc actgtaccac atgtctggctcccttctggg cattgtgggc tgcttgggca 900 ttggggccac cgtggtgctg aaacccaagttctcagctag ccagttctgg gacgattgcc 960 agaaacacag ggtgacagtg ttccagtacattggggagtt gtgccgatac ctcgtcaacc 1020 agcccccgag caaggcagag tttgaccataaggtgcgctt ggcagtgggc agtgggttgc 1080 gcccagacac ctgggagcgt ttcctgcggcgatttggacc tctgcagata ctggagacgt 1140 atggcatgac agagggcaac gtagctacgttcaattacac aggacggcag ggtgcagtgg 1200 ggcgagcttc ctggctttac aagcacatcttccccttctc cttgattcga tacgatgtca 1260 tgacagggga gcctattcgg aatgcccaggggcactgcat gaccacatct ccaggtgagc 1320 caggcctact ggtggcccca gtgagccagcagtccccctt cctgggctat gctggggctc 1380 cggagctggc caaggacaag ctgctgaaggatgtcttctg gtctggggac gttttcttca 1440 atactgggga cctcttggtc tgtgatgagcaaggctttct tcacttccac gatcgtactg 1500 gagacaccat caggtggaag ggagagaatgtggccacaac tgaagtggct gaggtcttgg 1560 agaccctgga cttccttcag gaggtgaacatctatggagt cacggtgcca gggcacgaag 1620 gcagggcagg catggcggcc ttggctctgcggcccccgca ggctctgaac ctggtgcagc 1680 tctacagcca tgtttctgag aacttgccaccgtatgcccg acctcggttt ctcaggctcc 1740 aggaatcttt ggccactact gagaccttcaaacagcagaa ggttaggatg gccaatgagg 1800 gctttgaccc cagtgtactg tctgacccactctatgttct ggaccaagat ataggggcct 1860 acctgcccct cacacctgcc cggtacagtgccctcctgtc tggagacctt cgaatctgaa 1920 accttccact tgagggaggg gctcggagggtacaggccac catggctgca ccagggaggg 1980 ttttcgggta tcttttgtat atggagtcattattttgtaa taaacagctg gagcttaaaa 2040 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaa 2087 7 613 PRT Mus musculus 7 Ala Ala Asp Pro Glu SerSer Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 Leu Ala Tyr Leu AlaArg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 Gly Ala Gln Arg PheSer Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 Ile Ala Arg Ala PheLeu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 Gly Ser Gly Arg GlySer Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80 Ala Gly Asp AlaAla Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95 Gly Ala Thr ValAla Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105 110 Ile Trp PheGly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115 120 125 Thr AlaLeu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly 130 135 140 AlaSer Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro 145 150 155160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp Ala Thr Gly 165170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro GlnAsn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe Thr Ser Gly Thr ThrGly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His Leu Lys Val Leu GlnCys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly Val His Gln Glu AspVal Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His Met Ser Gly Ser LeuLeu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly Ala Thr Val Val LeuLys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp Asp Asp Cys Gln LysHis Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly Glu Leu Cys Arg TyrLeu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 Glu Phe Asp His LysVal Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335 Asp Thr Trp GluArg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345 350 Glu Thr TyrGly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355 360 365 Gly ArgGln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile 370 375 380 PhePro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile 385 390 395400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro Gly Glu Pro Gly 405410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu Leu Lys Asp Val PheTrp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val CysAsp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp Arg Thr Gly Asp ThrIle Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala Thr Thr Glu Val AlaGlu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln Glu Val Asn Ile TyrGly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg Ala Gly Met Ala AlaLeu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn Leu Val Gln Leu TyrSer His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr Ala Arg Pro Arg PheLeu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 Thr Glu Thr Phe LysGln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575 Asp Pro Ser ValLeu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585 590 Gly Ala TyrLeu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595 600 605 Gly AspLeu Arg Ile 610 8 2301 DNA Mus musculus 8 cccacgcgtc cgcccacgcgtccggcatgg ccaagctggg cgtggaggcg gctctcatca 60 acaccaacct taggcgggatgccctgcgcc actgtcttga cacctcaaag gcacgagctc 120 tcatctttgg cagtgagatggcctcagcta tctgtgagat ccatgctagc ctggagccca 180 cactcagcct cttctgctctggatcctggg agcccagcac agtgcccgtc agcacagagc 240 atctggaccc tcttctggaagatgccccga agcacctgcc cagtcaccca gacaagggtt 300 ttacagataa gctcttctacatctacacat cgggcaccac ggggctaccc aaagctgcca 360 ttgtggtgca cagcaggtattatcgtatgg cttccctggt gtactatgga ttccgcatgc 420 ggcctgatga cattgtctatgactgcctcc ccctctacca ctcaagcagg aaacatcgtg 480 gggattggca gtgcttactccacggcatga ctgtggtgat ccggaagaag ttctcagcct 540 cccggttctg ggatgattgtatcaagtaca actgcacagt ggtacagtac attggcgagc 600 tctgccgcta cctcctgaaccagccacccc gtgaggctga gtctcggcac aaggtgcgca 660 tggcactggg caacggtctccggcagtcca tctggaccga cttctccagc cgtttccaca 720 tcccccaggt ggctgagttctatggggcca ctgaatgcaa ctgtagcctg ggcaactttg 780 acagccgggt gggggcctgtggcttcaata gccgcatcct gtcctttgtg taccctatcc 840 gtttggtacg tgtcaatgaggataccatgg aactgatccg gggacccgat ggagtctgca 900 ttccctgtca accaggtcagccaggccagc tggtgggtcg catcatccag caggaccctc 960 tgcgccgttt cgacgggtacctcaaccagg gtgccaacaa caagaagatt gctaatgatg 1020 tcttcaagaa gggggaccaagcctacctca ctggtgacgt cctggtgatg gatgagctgg 1080 gttacctgta cttccgagatcgcactgggg acacgttccg ctggaaaggg gagaatgtat 1140 ctaccactga ggtggagggcacactcagcc gcctgcttca tatggcagat gtggcagttt 1200 atggtgttga ggtgccaggaactgaaggcc gagcaggaat ggctgccgtt gcaagtccca 1260 tcagcaactg tgacctggagagctttgcac agaccttgaa aaaggagctg cctctgtatg 1320 cccgccccat cttcctgcgcttcttgcctg agctgcacaa gacagggacc ttcaagttcc 1380 agaagacaga gttgcggaaggagggctttg acccatctgt tgtgaaagac ccgctgttct 1440 atctggatgc tcggaagggctgctacgttg cactggacca ggaggcctat acccgcatcc 1500 aggcaggcga ggagaagctgtgatttcccc ctacatccct ctgagggcca gaagatgctg 1560 gattcagagc cctagcgtccaccccagagg gtcctgggca atgccagacc aaagctagca 1620 gggcccgcac ctccgcccctaggtgctgat ctcccctctc ccaaactgcc aagtgactca 1680 ctgccgcttc cccgaccctccagaggcttt ctgtgaaagt ctcatccaag ctgtgtcttc 1740 tggtccaggc gtggcccctggccccagggt ttctgatagg ctcctttagg atggtatctt 1800 gggtccagcg ggccagggtgtgggagagga gtcactaaga tccctccaat cagaagggag 1860 cttacaaagg aaccaaggcaaagcctgtag actcaggaag ctaagtggcc agagactata 1920 gtggccagtc atcccatgtccacagaggat cttggtccag agctgccaaa gtgtcacctc 1980 tccctgcctg cacctctggggaaaagagga cagcatgtgg ccactgggca cctgtctcaa 2040 gaagtcagga tcacacactcagtccttgtt tctccaggtt cccttgttct tgtctcgggg 2100 agggagggac gagtgtcctgtctgtccttc ctgcctgtct gtgagtctgt gttgcttctc 2160 catctgtcct agcctgagtgtgggtggaac aggcatgagg agagtgtggc tcaggggcca 2220 ataaactctg ccttgactcctcttaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 2280 aaaaaaaaaa aaaaaaaaaa a2301 9 506 PRT Mus musculus 9 His Ala Ser Ala His Ala Ser Gly Met AlaLys Leu Gly Val Glu Ala 1 5 10 15 Ala Leu Ile Asn Thr Asn Leu Arg ArgAsp Ala Leu Arg His Cys Leu 20 25 30 Asp Thr Ser Lys Ala Arg Ala Leu IlePhe Gly Ser Glu Met Ala Ser 35 40 45 Ala Ile Cys Glu Ile His Ala Ser LeuGlu Pro Thr Leu Ser Leu Phe 50 55 60 Cys Ser Gly Ser Trp Glu Pro Ser ThrVal Pro Val Ser Thr Glu His 65 70 75 80 Leu Asp Pro Leu Leu Glu Asp AlaPro Lys His Leu Pro Ser His Pro 85 90 95 Asp Lys Gly Phe Thr Asp Lys LeuPhe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110 Thr Gly Leu Pro Lys Ala AlaIle Val Val His Ser Arg Tyr Tyr Arg 115 120 125 Met Ala Ser Leu Val TyrTyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130 135 140 Val Tyr Asp Cys LeuPro Leu Tyr His Ser Ser Arg Lys His Arg Gly 145 150 155 160 Asp Trp GlnCys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys 165 170 175 Phe SerAla Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr 180 185 190 ValVal Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro 195 200 205Pro Arg Glu Ala Glu Ser Arg His Lys Val Arg Met Ala Leu Gly Asn 210 215220 Gly Leu Arg Gln Ser Ile Trp Thr Asp Phe Ser Ser Arg Phe His Ile 225230 235 240 Pro Gln Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys SerLeu 245 250 255 Gly Asn Phe Asp Ser Arg Val Gly Ala Cys Gly Phe Asn SerArg Ile 260 265 270 Leu Ser Phe Val Tyr Pro Ile Arg Leu Val Arg Val AsnGlu Asp Thr 275 280 285 Met Glu Leu Ile Arg Gly Pro Asp Gly Val Cys IlePro Cys Gln Pro 290 295 300 Gly Gln Pro Gly Gln Leu Val Gly Arg Ile IleGln Gln Asp Pro Leu 305 310 315 320 Arg Arg Phe Asp Gly Tyr Leu Asn GlnGly Ala Asn Asn Lys Lys Ile 325 330 335 Ala Asn Asp Val Phe Lys Lys GlyAsp Gln Ala Tyr Leu Thr Gly Asp 340 345 350 Val Leu Val Met Asp Glu LeuGly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360 365 Gly Asp Thr Phe Arg TrpLys Gly Glu Asn Val Ser Thr Thr Glu Val 370 375 380 Glu Gly Thr Leu SerArg Leu Leu His Met Ala Asp Val Ala Val Tyr 385 390 395 400 Gly Val GluVal Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val 405 410 415 Ala SerPro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr Leu 420 425 430 LysLys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Phe Leu 435 440 445Pro Glu Leu His Lys Thr Gly Thr Phe Lys Phe Gln Lys Thr Glu Leu 450 455460 Arg Lys Glu Gly Phe Asp Pro Ser Val Val Lys Asp Pro Leu Phe Tyr 465470 475 480 Leu Asp Ala Arg Lys Gly Cys Tyr Val Ala Leu Asp Gln Glu AlaTyr 485 490 495 Thr Arg Ile Gln Ala Gly Glu Glu Lys Leu 500 505 10 2277DNA Mus musculus 10 cactcatcag agctaagaga gactacacgc tctcatctacttcagaaaga gccaatgcca 60 tgggtatttg gaagaaacta accttactgc tgttgctgcttctgctggtt ggcctggggc 120 agcccccatg gccagcagct atggctctgg ccctgcgttggttcctggga gaccccacat 180 gccttgtgct gcttggcttg gcattgctgg gcagaccctggatcagctcc tggatgcccc 240 actggctgag cctggtagga gcagctctta ccttattcctattgcctcta cagccacccc 300 cagggctacg ctggctgcat aaagatgtgg ctttcaccttcaagatgctt ttctatggcc 360 taaagttcag gcgacgcctt aacaaacatc ctccagagacctttgtggat gctttagagc 420 ggcaagcact ggcatggcct gaccgggtgg ccttggtgtgtactgggtct gagggctcct 480 caatcacaaa tagccagctg gatgccaggt cctgtcaggcagcatgggtc ctgaaagcaa 540 agctgaagga tgccgtaatc cagaacacaa gagatgctgctgctatctta gttctcccgt 600 ccaagaccat ttctgctttg agtgtgtttc tggggttggccaagttgggc tgccctgtgg 660 cctggatcaa tccacacagc cgagggatgc ccttgctacactctgtacgg agctctgggg 720 ccagtgtgct gattgtggat ccagacctcc aggagaacctggaagaagtc cttcccaagc 780 tgctagctga gaacattcac tgcttctacc ttggccacagctcacccacc ccgggagtag 840 aggctctggg agcttccctg gatgctgcac cttctgacccagtacctgcc agccttcgag 900 ctacgattaa gtggaaatct cctgccatat tcatctttacttcagggacc actggactcc 960 caaagccagc catcttatca catgagcggg tcatacaagtgagcaacgtg ctgtccttct 1020 gtggatgcag agctgatgat gtggtctatg acgtcctacctctgtaccat acgatagggc 1080 ttgtccttgg attccttggc tgcttacaag ttggagccacctgtgtcctg gcccccaagt 1140 tctctgcctc ccgattctgg gctgagtgcc ggcagcatggcgtaacagtg atcttgtatg 1200 tgggtgaaat cctgcggtac ttgtgtaacg tccctgagcaaccagaagac aagatacata 1260 cagtgcgctt ggccatggga actggacttc gggcaaatgtgtggaaaaac ttccagcaac 1320 gctttggtcc cattcggatc tgggaattct acggatccacagagggcaat gtgggcttaa 1380 tgaactatgt gggccactgc ggggctgtgg gaaggaccagctgcatcctt cgaatgctga 1440 ctccctttga gcttgtacag ttcgacatag agacagcagagcctctgagg gacaaacagg 1500 gtttttgcat tcctgtggag ccaggaaagc caggacttcttttgaccaag gttcgaaaga 1560 accaaccctt cctgggctac cgtggttccc aggccgagtccaatcggaaa cttgttgcga 1620 atgtacgacg cgtaggagac ctgtacttca acactggggacgtgctgacc ttggaccagg 1680 aaggcttctt ctactttcaa gaccgccttg gtgacaccttccggtggaag ggcgaaaacg 1740 tatctactgg agaggtggag tgtgttttgt ctagcctagacttcctagag gaagtcaatg 1800 tctatggtgt gcctgtgcca gggtgtgagg gtaaggttggcatggctgct gtgaaactgg 1860 ctcctgggaa gacttttgat gggcagaagc tataccagcatgtccgctcc tggctccctg 1920 cctatgccac acctcatttc atccgtatcc aggattccctggagatcaca aacacctaca 1980 agctggtaaa gtcacggctg gtgcgtgagg gttttgatgtggggatcatt gctgaccccc 2040 tctacatact ggacaacaag gcccagacct tccggagtctgatgccagat gtgtaccagg 2100 ctgtgtgtga aggaacctgg aatctctgac cacctagccaactggaaggc aatccaaaag 2160 tgtagagatt gacactagtc agcttcacaa agttgtccgggttccagatg cccatggccc 2220 agtagtactt agagaataaa cttgaatgtg tatacaaaaaaaaaaaaaaa aaaaaaa 2277 11 662 PRT Mus musculus 11 Met Ala Leu Ala LeuArg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val 1 5 10 15 Leu Leu Gly LeuAla Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met 20 25 30 Pro His Trp LeuSer Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu 35 40 45 Pro Leu Gln ProPro Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala 50 55 60 Phe Thr Phe LysMet Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu 65 70 75 80 Asn Lys HisPro Pro Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala 85 90 95 Leu Ala TrpPro Asp Arg Val Ala Leu Val Cys Thr Gly Ser Glu Gly 100 105 110 Ser SerIle Thr Asn Ser Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala 115 120 125 TrpVal Leu Lys Ala Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg 130 135 140Asp Ala Ala Ala Ile Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu 145 150155 160 Ser Val Phe Leu Gly Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile165 170 175 Asn Pro His Ser Arg Gly Met Pro Leu Leu His Ser Val Arg SerSer 180 185 190 Gly Ala Ser Val Leu Ile Val Asp Pro Asp Leu Gln Glu AsnLeu Glu 195 200 205 Glu Val Leu Pro Lys Leu Leu Ala Glu Asn Ile His CysPhe Tyr Leu 210 215 220 Gly His Ser Ser Pro Thr Pro Gly Val Glu Ala LeuGly Ala Ser Leu 225 230 235 240 Asp Ala Ala Pro Ser Asp Pro Val Pro AlaSer Leu Arg Ala Thr Ile 245 250 255 Lys Trp Lys Ser Pro Ala Ile Phe IlePhe Thr Ser Gly Thr Thr Gly 260 265 270 Leu Pro Lys Pro Ala Ile Leu SerHis Glu Arg Val Ile Gln Val Ser 275 280 285 Asn Val Leu Ser Phe Cys GlyCys Arg Ala Asp Asp Val Val Tyr Asp 290 295 300 Val Leu Pro Leu Tyr HisThr Ile Gly Leu Val Leu Gly Phe Leu Gly 305 310 315 320 Cys Leu Gln ValGly Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala 325 330 335 Ser Arg PheTrp Ala Glu Cys Arg Gln His Gly Val Thr Val Ile Leu 340 345 350 Tyr ValGly Glu Ile Leu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro 355 360 365 GluAsp Lys Ile His Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg 370 375 380Ala Asn Val Trp Lys Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile 385 390395 400 Trp Glu Phe Tyr Gly Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr405 410 415 Val Gly His Cys Gly Ala Val Gly Arg Thr Ser Cys Ile Leu ArgMet 420 425 430 Leu Thr Pro Phe Glu Leu Val Gln Phe Asp Ile Glu Thr AlaGlu Pro 435 440 445 Leu Arg Asp Lys Gln Gly Phe Cys Ile Pro Val Glu ProGly Lys Pro 450 455 460 Gly Leu Leu Leu Thr Lys Val Arg Lys Asn Gln ProPhe Leu Gly Tyr 465 470 475 480 Arg Gly Ser Gln Ala Glu Ser Asn Arg LysLeu Val Ala Asn Val Arg 485 490 495 Arg Val Gly Asp Leu Tyr Phe Asn ThrGly Asp Val Leu Thr Leu Asp 500 505 510 Gln Glu Gly Phe Phe Tyr Phe GlnAsp Arg Leu Gly Asp Thr Phe Arg 515 520 525 Trp Lys Gly Glu Asn Val SerThr Gly Glu Val Glu Cys Val Leu Ser 530 535 540 Ser Leu Asp Phe Leu GluGlu Val Asn Val Tyr Gly Val Pro Val Pro 545 550 555 560 Gly Cys Glu GlyLys Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly 565 570 575 Lys Thr PheAsp Gly Gln Lys Leu Tyr Gln His Val Arg Ser Trp Leu 580 585 590 Pro AlaTyr Ala Thr Pro His Phe Ile Arg Ile Gln Asp Ser Leu Glu 595 600 605 IleThr Asn Thr Tyr Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly 610 615 620Phe Asp Val Gly Ile Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys 625 630635 640 Ala Gln Thr Phe Arg Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys645 650 655 Glu Gly Thr Trp Asn Leu 660 12 1622 DNA Homo sapiensmisc_feature (1)...(1622) n = A,T,C or G 12 atgggattga ctctttcctggacaaagtgg atgaagtatc aactgaacct atcccagagt 60 catggaggtc tgaagtcactttttccactc ctgccttata catttatact tctggaacca 120 caggtcttcc aaaagcagccatgatcactc atcagcgcat atggtatgga actggcctca 180 cttttgtaag cggattgaaggcagatgatg tcatctatat cactctgccc ttttaccaca 240 gtgctgcact actgattggcattcacggat gtattgtggc tggtgctact cttgccttgc 300 ggactaaatt ttcagccagccagttttggg atgactgcag aaaatacaac gtcactgtca 360 ttcagtatat cggtgaactgcttcggtatt tatgcaactc accacagaaa ccaaatgacc 420 gtgatcataa agtgagactggcactgggaa atggcttacg aggagatgtg tggagacaat 480 ttgtcaagag atttggggacatatgcatct atgagttcta tgctgccact gaaggcaata 540 ttggatttat gaattatgcgagaaaagttg gtgctgttgg aagagtaaac tacctacaga 600 aaaaaatcat aacttatgacctgattaaat atgatgtgga gaaagatgaa cctgtccgtg 660 atgaaaatgg atattgcgtcagagttccca aaggtgaagt tggacttctg gtttgcaaaa 720 tcacacaact tacaccatttaatggctatg ctggagcaaa ggctcagaca gagaagaaaa 780 aactgagaga tgtctttaagaaaggagacc tctatttcaa cagtggagat ctcttaatgg 840 ttgaccatga aaatttcatctatttccacg acagagttgg agatacattc cggtggaaag 900 gggaaaatgt ggccaccactgaagttgctg atatagttgg actggttgat ttttttccaa 960 ggaagtaaaa tgtttatgggagtgcatggg ccaagatnat ggaggttcga attggcatgg 1020 cnttccnttc aaaatggaaagaaaaccatg gaatttgatg gaaagaaatt ttttcagnac 1080 attgctgata accnacctagttatgcaagg ccccggtttt ntaagaanac aggacaccat 1140 tgagatcact ggaatttttaaacaccgcaa aatgaccttt ggtggaggag ggctttaacc 1200 cngctgtcat caaagatgccttgtattttc ttggatgaca cagcaaaaat gtatgtgcct 1260 atgactgagg acatntataatgccataagt gntaaaaccc tgaaattntg aatattccca 1320 ggaggataat tcaacatttccagaaagaaa ctgaatggac agccacttga tataatccaa 1380 ctttaatttg attgaagattgtgaggaaat tttgtaggaa atttgcatac ccgtaaaggg 1440 agactttttt aaataacagttgagtctttg caagtaaaaa gatttagaga ttattatttt 1500 tcagtgtgca cctactgtttgtatttgcaa actgagcttg ttggagggaa ggcattattt 1560 tttaaaatac ttagtaaattaaagaacacc aacatgtgaa aaaaaaaaaa aaaaaaaaaa 1620 aa 1622 13 286 PRT Homosapiens 13 Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala MetIle 1 5 10 15 Thr His Gln Arg Ile Trp Tyr Gly Thr Gly Leu Thr Phe ValSer Gly 20 25 30 Leu Lys Ala Asp Asp Val Ile Tyr Ile Thr Leu Pro Phe TyrHis Ser 35 40 45 Ala Ala Leu Leu Ile Gly Ile His Gly Cys Ile Val Ala GlyAla Thr 50 55 60 Leu Ala Leu Arg Thr Lys Phe Ser Ala Ser Gln Phe Trp AspAsp Cys 65 70 75 80 Arg Lys Tyr Asn Val Thr Val Ile Gln Tyr Ile Gly GluLeu Leu Arg 85 90 95 Tyr Leu Cys Asn Ser Pro Gln Lys Pro Asn Asp Arg AspHis Lys Val 100 105 110 Arg Leu Ala Leu Gly Asn Gly Leu Arg Gly Asp ValTrp Arg Gln Phe 115 120 125 Val Lys Arg Phe Gly Asp Ile Cys Ile Tyr GluPhe Tyr Ala Ala Thr 130 135 140 Glu Gly Asn Ile Gly Phe Met Asn Tyr AlaArg Lys Val Gly Ala Val 145 150 155 160 Gly Arg Val Asn Tyr Leu Gln LysLys Ile Ile Thr Tyr Asp Leu Ile 165 170 175 Lys Tyr Asp Val Glu Lys AspGlu Pro Val Arg Asp Glu Asn Gly Tyr 180 185 190 Cys Val Arg Val Pro LysGly Glu Val Gly Leu Leu Val Cys Lys Ile 195 200 205 Thr Gln Leu Thr ProPhe Asn Gly Tyr Ala Gly Ala Lys Ala Gln Thr 210 215 220 Glu Lys Lys LysLeu Arg Asp Val Phe Lys Lys Gly Asp Leu Tyr Phe 225 230 235 240 Asn SerGly Asp Leu Leu Met Val Asp His Glu Asn Phe Ile Tyr Phe 245 250 255 HisAsp Arg Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 260 265 270Thr Thr Glu Val Ala Asp Ile Val Gly Leu Val Asp Phe Phe 275 280 285 14753 DNA Homo sapiens 14 caattcggga cccccagggg cactgtatgg ccacatctccaggtgagcca ggggaagttg 60 ctaaaggatg tcttccggcc tggggatgtt ttcttcaacactggggacct gctggtctgc 120 gatgaccaag gttttctccg cttccatgat cgtactggagacaccttcag gtggaaaggg 180 gagaatgtgg ccacaaccga ggtggcagag gtcttcgaggccctagattt tcttcaggag 240 gtgaacgtct atggagtcac tgtgccaggg catgaaggcagggctggaat ggcagcccta 300 gttctgcgtc ccccccacgc tttggacctt atgcagctctacacccacgt gtctgagaac 360 ttgccacctt atgcccggcc ccgattcctc aggctccaggagtctttggc caccacagag 420 accttcaaac agcagaaagt tcggatggca aatgagggcttcgaccccag caccctgtct 480 gacccactgt acgttctgga ccaggctgta ggtgcctacctgcccctcac aactgcccgg 540 tacagcgccc tcctggcagg aaaccttcga atctgagaacttccacacct gaggcacctg 600 agagaggaac tctgtggggt gggggccgtt gcaggtgtactgggctgtca gggatctttt 660 ctataccaga actgcggtca ctattttgta ataaatgtggctggagctga tccagctgtc 720 tctgacctac aaaaaaaaaa aaaaaaaaaa aaa 753 15191 PRT Homo sapiens 15 Gln Phe Gly Thr Pro Arg Gly Thr Val Trp Pro HisLeu Gln Val Ser 1 5 10 15 Gln Gly Lys Leu Leu Lys Asp Val Phe Arg ProGly Asp Val Phe Phe 20 25 30 Asn Thr Gly Asp Leu Leu Val Cys Asp Asp GlnGly Phe Leu Arg Phe 35 40 45 His Asp Arg Thr Gly Asp Thr Phe Arg Trp LysGly Glu Asn Val Ala 50 55 60 Thr Thr Glu Val Ala Glu Val Phe Glu Ala LeuAsp Phe Leu Gln Glu 65 70 75 80 Val Asn Val Tyr Gly Val Thr Val Pro GlyHis Glu Gly Arg Ala Gly 85 90 95 Met Ala Ala Leu Val Leu Arg Pro Pro HisAla Leu Asp Leu Met Gln 100 105 110 Leu Tyr Thr His Val Ser Glu Asn LeuPro Pro Tyr Ala Arg Pro Arg 115 120 125 Phe Leu Arg Leu Gln Glu Ser LeuAla Thr Thr Glu Thr Phe Lys Gln 130 135 140 Gln Lys Val Arg Met Ala AsnGlu Gly Phe Asp Pro Ser Thr Leu Ser 145 150 155 160 Asp Pro Leu Tyr ValLeu Asp Gln Ala Val Gly Ala Tyr Leu Pro Leu 165 170 175 Thr Thr Ala ArgTyr Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile 180 185 190 16 734 DNA Homosapiens misc_feature (1)...(734) n = A,T,C or G 16 tcaagtacaa ctgcacgattgtcatancat tggtgaactg tgccgntacc tcctgaacca 60 gccaccgcgg gaggcagaaaaccagcacca ggttcgcatg gcactaggca atggcctccg 120 gcagtccatc tggaccaacttttccagccg cttccacata ccccaggtgg ctgagttyta 180 cggggccaca gagtgcaactgtagcctggg caacttcgac agccaggtgg gggcctgtgg 240 tttcaatagc cgcatcctgtccttcgtgta ccccatccgg ttggtacgtg tcaacgagga 300 caccatggag ctgatccgggggcccgacgg cgtctgcatt ccctgccagc caggtgagcc 360 gggccagctg gtgggccgcatcatccagaa agaccccctg cgccgcttcg atggctacct 420 caaccagggc gccaacaacaagaagattgc caaggatgtc ttcaagaagg gggaccaggc 480 ctaccttact ggtgatgtgctggtgatgga cgagctgggc tacctgtact tccgagaccg 540 cactggggac acgttccgctggaaaggtga gaacgtgtcc accaccgagg tggaaggcac 600 actcagccgc ctgctggacatggctgacgt ggccgtgtat ggtgtcgagg tgccaggaac 660 cgagggccgg gccggaatggctgctgtggc cagccccact ggcaactgtg acctgggagc 720 gctttgctca ggtc 734 17213 PRT Homo sapiens 17 Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln ProPro Arg Glu Ala 1 5 10 15 Glu Asn Gln His Gln Val Arg Met Ala Leu GlyAsn Gly Leu Arg Gln 20 25 30 Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe HisIle Pro Gln Val Ala 35 40 45 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys SerLeu Gly Asn Phe Asp 50 55 60 Ser Gln Val Gly Ala Cys Gly Phe Asn Ser ArgIle Leu Ser Phe Val 65 70 75 80 Tyr Pro Ile Arg Leu Val Arg Val Asn GluAsp Thr Met Glu Leu Ile 85 90 95 Arg Gly Pro Asp Gly Val Cys Ile Pro CysGln Pro Gly Glu Pro Gly 100 105 110 Gln Leu Val Gly Arg Ile Ile Gln LysAsp Pro Leu Arg Arg Phe Asp 115 120 125 Gly Tyr Leu Asn Gln Gly Ala AsnAsn Lys Lys Ile Ala Lys Asp Val 130 135 140 Phe Lys Lys Gly Asp Gln AlaTyr Leu Thr Gly Asp Val Leu Val Met 145 150 155 160 Asp Glu Leu Gly TyrLeu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe 165 170 175 Arg Trp Lys GlyGlu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu 180 185 190 Ser Arg LeuLeu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val 195 200 205 Pro GlyThr Glu Gly 210 18 1278 DNA Homo sapiens misc_feature (1)...(1278) n =A,T,C or G 18 cntgcctctt gtaccacgtg atgggacttt gtcgttggga tcctcggctgcttagatctc 60 ggagccacct gtgttctggc ccccaagttc tctacttcct gcttctgggatgactgtcgg 120 cagcatggcg tgacagtgat cctgtatgtg ggcgagctcc tgcgntacttgtgtaacatt 180 ccccagcaac cagaggaccg gacacataca gtccgcctgg caatgggcaatggactacgg 240 gctgatgtgt ggggagacct tccagcagcg tttcggtcct atttcggatctngggaagtc 300 ttacgggcty ccacagaagg gcaacatggg gctttagttc aactattgttgggggcgctg 360 cggggscctg grggcaaaga tggagcttgc ctcctccgaa tgctgtccccctttgagctg 420 gtgcagttcg acatggaggc ggcggagcct gtgagggaca atcagggcttctgcatccct 480 gtagggctag gggagccggg gctgctgttg accaaggtgg taagccagcaacccttcgtg 540 ggctaccgcg gcccccgaga gctgtcggaa cggaagctgg tgcgcaacgtgcggcaatcg 600 ggcgacgttt actacaacac cggggacgta ctggccatgg accgcgaaggcttcctctac 660 ttccgcgacc gactcgggga caccttccga tggaagggcg agaacgtgtccacgcacgag 720 gtggagggcg tgttgtcgca ggtggacttc ttgcaacagg ttaacgtgtatggcgtgtgc 780 gtgccaggtt gtgagggtaa ggtgggcatg gctgctgtgg cattagcccccggccagact 840 ttcgacgggg agaagttgta ccagcacgtt cgcgcttggc tccctgcctacgctaccccc 900 catttcatcc gcatccagga cgccatggag gtcaccagca cgttcaaactgatgaagacc 960 cggttggtgc gtgagggctt caatgtgggg atcgtggttg accctctgtttgtactggac 1020 aaccgggccc agtccttccg gcccctgacg gcagaaatgt accaggctgtgtgtgaggga 1080 acctggaggc tctgatcacc tggccaaccc actggggtag ggatcaaagccagccacccc 1140 caccccaaca cactcggtgt ccctttcatc ctgggcctgt gtgaatcccagcctggccat 1200 accctcaacc tcagtgggct ggaaatgaca gtgggccctg tagcagtggcagaataaact 1260 cagmtgygtt cacagaaa 1278 19 199 PRT Homo sapiens 19 GluGly Gln His Gly Ala Leu Val Gln Leu Leu Leu Gly Ala Leu Arg 1 5 10 15Gly Pro Gly Gly Lys Asp Gly Ala Cys Leu Leu Arg Met Leu Ser Pro 20 25 30Phe Glu Leu Val Gln Phe Asp Met Glu Ala Ala Glu Pro Val Arg Asp 35 40 45Asn Gln Gly Phe Cys Ile Pro Val Gly Leu Gly Glu Pro Gly Leu Leu 50 55 60Leu Thr Lys Val Val Ser Gln Gln Pro Phe Val Gly Tyr Arg Gly Pro 65 70 7580 Arg Glu Leu Ser Glu Arg Lys Leu Val Arg Asn Val Arg Gln Ser Gly 85 9095 Asp Val Tyr Tyr Asn Thr Gly Asp Val Leu Ala Met Asp Arg Glu Gly 100105 110 Phe Leu Tyr Phe Arg Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly115 120 125 Glu Asn Val Ser Thr His Glu Val Glu Gly Val Leu Ser Gln ValAsp 130 135 140 Phe Leu Gln Gln Val Asn Val Tyr Gly Val Cys Val Pro GlyCys Glu 145 150 155 160 Gly Lys Val Gly Met Ala Ala Val Ala Leu Ala ProGly Gln Thr Phe 165 170 175 Asp Gly Glu Lys Leu Tyr Gln His Val Arg AlaTrp Leu Pro Ala Tyr 180 185 190 Ala Thr Pro His Phe Ile Arg 195 20 1361DNA Homo sapiens 20 cgcttgtgtg ttaaagaaga aattttcagc aagccagttttggagtgact gcaagaagta 60 tgatgtgact gtgtttcagt atattggaga actttgtcgctacctttgca aacaatctaa 120 gagagaagga gaaaaggatc ataaggtgcg tttggcaattggaaatggca tacggagtga 180 tgtatggaga gaatttttag acagatttgg aaatataaaggtgtgtgaac tttatgcagc 240 taccgaatca agcatatctt tcatgaacta cactgggagaattggagcaa ttgggagaac 300 aaatttgttt tacaaacttc tttccacttt tgacttaataaagtatgact ttcagaaaga 360 tgaacccatg agaaatgagc agggttgggt attcatgagaaaaaggagac ctggacttct 420 catttctcga gtgaatgcaa aaaatccctt ctttggctatgctgggcctt ataagcacac 480 aaaagacaaa ttgctttgtg atgtttttaa gaagggagatgtttacctta atactggaga 540 cttaatagtc caggatcagg acaatttcct ttatttttgggaccgtactg gagacacttt 600 cagatggaaa ggagaaaatg tcgcaaccac tgaggttgctgatgttattg gaatgttgga 660 tttcatacag gaagcaaacg tctatggtgt ggctatatcaggttatgaag gaagagcagg 720 aatggcttct attattttaa aaccaaatac atctttagatttggaaaaag tttatgaaca 780 agttgtaaca tttctaccag cttatgcttg tccacgatttttaagaattc aggaaaaaat 840 ggaagcaaca ggaacattca aactattgaa gcatcagttggtggaagatg gatttaatcc 900 actgaaaatt tctgaaccac tttacttcat ggataacttgaaaaagtctt atgttctact 960 gaccagggaa ctttatgatc aaataatgtt aggggaaataaaactttaag atttttatat 1020 ctagaacttt catatgcttt cttaggaaga gtgagaggggggtatatgat tctttatgaa 1080 atggggaaag ggagctaaca ttaattatgc atgtactatatttccttaat atgagagata 1140 attttttaat tgcataagaa ttttaatttc ttttaattgatataaacaga gttgattatt 1200 ctttttatct atttggagat tcagtgcata actaagtattttccttaata ctaaagattt 1260 taaataataa atagtggcta gcggtttgga caatcactaaaaatgtactt tctaataagt 1320 aaaatttcta attttgaata aaagattaaa ttttactgaa a1361 21 335 PRT Homo sapiens 21 Ala Cys Val Leu Lys Lys Lys Phe Ser AlaSer Gln Phe Trp Ser Asp 1 5 10 15 Cys Lys Lys Tyr Asp Val Thr Val PheGln Tyr Ile Gly Glu Leu Cys 20 25 30 Arg Tyr Leu Cys Lys Gln Ser Lys ArgGlu Gly Glu Lys Asp His Lys 35 40 45 Val Arg Leu Ala Ile Gly Asn Gly IleArg Ser Asp Val Trp Arg Glu 50 55 60 Phe Leu Asp Arg Phe Gly Asn Ile LysVal Cys Glu Leu Tyr Ala Ala 65 70 75 80 Thr Glu Ser Ser Ile Ser Phe MetAsn Tyr Thr Gly Arg Ile Gly Ala 85 90 95 Ile Gly Arg Thr Asn Leu Phe TyrLys Leu Leu Ser Thr Phe Asp Leu 100 105 110 Ile Lys Tyr Asp Phe Gln LysAsp Glu Pro Met Arg Asn Glu Gln Gly 115 120 125 Trp Val Phe Met Arg LysArg Arg Pro Gly Leu Leu Ile Ser Arg Val 130 135 140 Asn Ala Lys Asn ProPhe Phe Gly Tyr Ala Gly Pro Tyr Lys His Thr 145 150 155 160 Lys Asp LysLeu Leu Cys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu 165 170 175 Asn ThrGly Asp Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe 180 185 190 TrpAsp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 195 200 205Thr Thr Glu Val Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu 210 215220 Ala Asn Val Tyr Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly 225230 235 240 Met Ala Ser Ile Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu GluLys 245 250 255 Val Tyr Glu Gln Val Val Thr Phe Leu Pro Ala Tyr Ala CysPro Arg 260 265 270 Phe Leu Arg Ile Gln Glu Lys Met Glu Ala Thr Gly ThrPhe Lys Leu 275 280 285 Leu Lys His Gln Leu Val Glu Asp Gly Phe Asn ProLeu Lys Ile Ser 290 295 300 Glu Pro Leu Tyr Phe Met Asp Asn Leu Lys LysSer Tyr Val Leu Leu 305 310 315 320 Thr Arg Glu Leu Tyr Asp Gln Ile MetLeu Gly Glu Ile Lys Leu 325 330 335 22 2007 DNA Mycobacteriumtuberculosis 22 tagtcgataa cgtcaaggac gctctgcggg cctgcgcacc ttcctgaggttggtcgacaa 60 ccaattcgac atttcgcaaa cgaatcgagg gcttacgtgt ccgattactacggcggcgca 120 cacacaacgg tcaggctgat cgacctggca actcggatgc cgcgagtgttggcggacacg 180 ccggtgattg tgcgtggggc aatgaccggg ctgctggccc ggccgaattccaaggcgtcg 240 atcggcacgg tgttccagga ccgggccgct cgctacggtg accgagtcttcctgaaattc 300 ggcgatcagc agctgaccta ccgcgacgct aacgccaccg ccaaccggtacgccgcggtg 360 ttggccgccc gcggcgtcgg ccccggcgac gtcgttggca tcatgttgcgtaactcaccc 420 agcacagtct tggcgatgct ggccacggtc aagtgcggcg ctatcgccggcatgctcaac 480 taccaccagc gcggcgaggt gttggcgcac agcctgggtc tgctggacgcgaaggtactg 540 atcgcagagt ccgacttggt cagcgccgtc gccgaatgcg gcgcctcgcgcggccgggta 600 gcgggcgacg tgctgaccgt cgaggacgtg gagcgattcg ccacaacggcgcccgccacc 660 aacccggcgt cggcgtcggc ggtgcaagcc aaagacaccg cgttctacatcttcacctcg 720 ggcaccaccg gatttcccaa ggccagtgtc atgacgcatc atcggtggctgcgggcgctg 780 gccgtcttcg gagggatggg gctgcggctg aagggttccg acacgctctacagctgcctg 840 ccgctgtacc acaacaacgc gttaacggtc gcggtgtcgt cggtgatcaattctggggcg 900 accctggcgc tgggtaagtc gttttcggcg tcgcggttct gggatgaggtgattgccaac 960 cgggcgacgg cgttcgtcta catcggcgaa atctgccgtt atctgctcaaccagccggcc 1020 aagccgaccg accgtgccca ccaggtgcgg gtgatctgcg gtaacgggctgcggccggag 1080 atctgggatg agttcaccac ccgcttcggg gtcgcgcggg tgtgcgagttctacgccgcc 1140 agcgaaggca actcggcctt tatcaacatc ttcaacgtgc ccaggaccgccggggtatcg 1200 ccgatgccgc ttgcctttgt ggaatacgac ctggacaccg gcgatccgctgcgggatgcg 1260 agcgggcgag tgcgtcgggt acccgacggt gaacccggcc tgttgcttagccgggtcaac 1320 cggctgcagc cgttcgacgg ctacaccgac ccggttgcca gcgaaaagaagttggtgcgc 1380 aacgcttttc gagatggcga ctgttggttc aacaccggtg acgtgatgagcccgcagggc 1440 atgggccatg ccgccttcgt cgatcggctg ggcgacacct tccgctggaagggcgagaat 1500 gtcgccacca ctcaggtcga agcggcactg gcctccgacc agaccgtcgaggagtgcacg 1560 gtctacggcg tccagattcc gcgcaccggc gggcgcgccg gaatggccgcgatcacactg 1620 cgcgctggcg ccgaattcga cggccaggcg ctggcccgaa cggtttacggtcacttgccc 1680 ggctatgcac ttccgctctt tgttcgggta gtggggtcgc tggcgcacaccacgacgttc 1740 aagagtcgca aggtggagtt gcgcaaccag gcctatggcg ccgacatcgaggatccgctg 1800 tacgtactgg ccggcccgga cgaaggatat gtgccgtact acgccgaataccctgaggag 1860 gtttcgctcg gaaggcgacc gcagggctag cggattccgg gcgcagtctcgatacccgca 1920 ctggacgctc gacggtaacc aggcactatg gatgcgtgcg ttcaacaccgccggcctcag 1980 ccggtcgttc aacaccgccg gcgttag 2007 23 597 PRTMycobacterium tuberculosis 23 Met Ser Asp Tyr Tyr Gly Gly Ala His ThrThr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val LeuAla Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu AlaArg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg AlaAla Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln LeuThr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala ValLeu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met LeuArg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val LysCys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly GluVal Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu IleAla Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly AlaSer Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp ValGlu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 AlaSer Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn AlaLeu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr LeuAla Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu ValIle Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile CysArg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala HisGln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu IleTrp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys GluPhe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile PheAsn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala PheVal Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala SerGly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu LeuLeu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr AspPro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 AspGly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile ProArg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg AlaGly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr GlyHis Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val GlySer Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu LeuArg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu TyrVal Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala GluTyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595 243704 DNA Homo sapiens CDS (175)...(2112) 24 tcgacccacg gcgtccgggaccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtcc aggagtctgcagaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcct gcctgagcttctgggagact gaaggcacgg cttgcagctt cagg atg 177 Met 1 cgg gct ccg ggt gcgggc gcg gcc tcg gtg gtc tcg ctg gcg ctg ttg 225 Arg Ala Pro Gly Ala GlyAla Ala Ser Val Val Ser Leu Ala Leu Leu 5 10 15 tgg ctg ctg ggg ctg ccgtgg acc tgg agc gcg gca gcg gcg ctc ggc 273 Trp Leu Leu Gly Leu Pro TrpThr Trp Ser Ala Ala Ala Ala Leu Gly 20 25 30 gtg tac gtg ggc agc ggc ggctgg cgc ttc ctg cgc atc gtc tgc aag 321 Val Tyr Val Gly Ser Gly Gly TrpArg Phe Leu Arg Ile Val Cys Lys 35 40 45 acc gcg agg cga gac ctc ttc ggtctc tct gtg ctg atc cgc gtg cgc 369 Thr Ala Arg Arg Asp Leu Phe Gly LeuSer Val Leu Ile Arg Val Arg 50 55 60 65 ctg gag ctg cgg cgg cac cag cgtgcc ggc cac acc atc ccg cgc atc 417 Leu Glu Leu Arg Arg His Gln Arg AlaGly His Thr Ile Pro Arg Ile 70 75 80 ttt cag gcg gta gtg cag cga cag cccgag cgc ctg gcg ctg gtg gat 465 Phe Gln Ala Val Val Gln Arg Gln Pro GluArg Leu Ala Leu Val Asp 85 90 95 gcc ggg acc ggc gag tgc tgg acc ttt gcgcag ctg gac gcc tac tcc 513 Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala GlnLeu Asp Ala Tyr Ser 100 105 110 aat gcg gta gcc aac ctc ttc cgc cag ctgggc ttc gcg ccg ggc gac 561 Asn Ala Val Ala Asn Leu Phe Arg Gln Leu GlyPhe Ala Pro Gly Asp 115 120 125 gtg gtg gcc atc ttc ctg gag ggc cgg ccggag ttc gtg ggg ctg tgg 609 Val Val Ala Ile Phe Leu Glu Gly Arg Pro GluPhe Val Gly Leu Trp 130 135 140 145 ctg ggc ctg gcc aag gcg ggc atg gaggcc gcg ctg ctc aac gtg aac 657 Leu Gly Leu Ala Lys Ala Gly Met Glu AlaAla Leu Leu Asn Val Asn 150 155 160 ctg cgg cgc gag ccc ctg gcc ttc tgcctg ggc acc tcg ggc gct aag 705 Leu Arg Arg Glu Pro Leu Ala Phe Cys LeuGly Thr Ser Gly Ala Lys 165 170 175 gcc ctg atc ttt gga gga gaa atg gtggcg gcg gtg gcc gaa gtg agc 753 Ala Leu Ile Phe Gly Gly Glu Met Val AlaAla Val Ala Glu Val Ser 180 185 190 ggg cat ctg ggg aaa agt ttg atc aagttc tgc tct gga gac ttg ggg 801 Gly His Leu Gly Lys Ser Leu Ile Lys PheCys Ser Gly Asp Leu Gly 195 200 205 ccc gag ggc atc ttg ccg gac acc cacctc ctg gac ccg ctg ctg aag 849 Pro Glu Gly Ile Leu Pro Asp Thr His LeuLeu Asp Pro Leu Leu Lys 210 215 220 225 gag gcc tct act gcc ccc ttg gcacag atc ccc agc aag ggc atg gac 897 Glu Ala Ser Thr Ala Pro Leu Ala GlnIle Pro Ser Lys Gly Met Asp 230 235 240 gat cgt ctt ttc tac atc tac acgtcg ggg acc acc ggg ctg ccc aag 945 Asp Arg Leu Phe Tyr Ile Tyr Thr SerGly Thr Thr Gly Leu Pro Lys 245 250 255 gct gcc att gtc gtg cac agc aggtac tac cgc atg gca gcc ttc ggc 993 Ala Ala Ile Val Val His Ser Arg TyrTyr Arg Met Ala Ala Phe Gly 260 265 270 cac cac gcc tac cgc atg cag gcggct gac gtg ctc tat gac tgc ctg 1041 His His Ala Tyr Arg Met Gln Ala AlaAsp Val Leu Tyr Asp Cys Leu 275 280 285 ccc ctg tac cac tcg gca gga aacatc atc ggc gtg ggg cag tgt ctc 1089 Pro Leu Tyr His Ser Ala Gly Asn IleIle Gly Val Gly Gln Cys Leu 290 295 300 305 atc tat ggg ctg aca gtc gtcctc cgc aag aaa ttc tcg gcc agc cgc 1137 Ile Tyr Gly Leu Thr Val Val LeuArg Lys Lys Phe Ser Ala Ser Arg 310 315 320 ttc tgg gac gac tgc atc aagtac aac tgc acg gtg gtt cag tac atc 1185 Phe Trp Asp Asp Cys Ile Lys TyrAsn Cys Thr Val Val Gln Tyr Ile 325 330 335 ggg gag atc tgc cgc tac ctgctg aag cag ccg gtg cgc gag gcg gag 1233 Gly Glu Ile Cys Arg Tyr Leu LeuLys Gln Pro Val Arg Glu Ala Glu 340 345 350 agg cga cac cgc gtg cgc ctggcg gtg ggg aac ggg ctg cgt cct gcc 1281 Arg Arg His Arg Val Arg Leu AlaVal Gly Asn Gly Leu Arg Pro Ala 355 360 365 atc tgg gag gag ttc acg gagcgc ttc ggc gta cgc caa atc ggg gag 1329 Ile Trp Glu Glu Phe Thr Glu ArgPhe Gly Val Arg Gln Ile Gly Glu 370 375 380 385 ttc tac ggc gcc acc gagtgc aac tgc agc att gcc aac atg gac ggc 1377 Phe Tyr Gly Ala Thr Glu CysAsn Cys Ser Ile Ala Asn Met Asp Gly 390 395 400 aag gtc ggc tcc tgt ggtttc aac agc cgc atc ctg ccc cac gtg tac 1425 Lys Val Gly Ser Cys Gly PheAsn Ser Arg Ile Leu Pro His Val Tyr 405 410 415 ccc atc cgg ctg gtg aaggtc aat gag gac aca atg gag ctg ctg cgg 1473 Pro Ile Arg Leu Val Lys ValAsn Glu Asp Thr Met Glu Leu Leu Arg 420 425 430 gat gcc cag ggc ctc tgcatc ccc tgc cag gcc ggg gag cct ggc ctc 1521 Asp Ala Gln Gly Leu Cys IlePro Cys Gln Ala Gly Glu Pro Gly Leu 435 440 445 ctt gtg ggt cag atc aaccaa cag gac ccg ctg cgc cgc ttc gat ggc 1569 Leu Val Gly Gln Ile Asn GlnGln Asp Pro Leu Arg Arg Phe Asp Gly 450 455 460 465 tat gtc agc gag agcgcc acc agc aag aag atc gcc cac agc gtc ttc 1617 Tyr Val Ser Glu Ser AlaThr Ser Lys Lys Ile Ala His Ser Val Phe 470 475 480 agc aag ggc gac agcgcc tac ctc tca ggt gac gtg cta gtg atg gat 1665 Ser Lys Gly Asp Ser AlaTyr Leu Ser Gly Asp Val Leu Val Met Asp 485 490 495 gag ctg ggc tac atgtac ttc cgg gac cgt agc ggg gac acc ttc cgc 1713 Glu Leu Gly Tyr Met TyrPhe Arg Asp Arg Ser Gly Asp Thr Phe Arg 500 505 510 tgg cga ggg gag aacgtc tcc acc acc gag gtg gag ggc gtg ctg agc 1761 Trp Arg Gly Glu Asn ValSer Thr Thr Glu Val Glu Gly Val Leu Ser 515 520 525 cgc ctg ctg ggc cagaca gac gtg gcc gtc tat ggg gtg gct gtt cca 1809 Arg Leu Leu Gly Gln ThrAsp Val Ala Val Tyr Gly Val Ala Val Pro 530 535 540 545 gga gtg gag ggtaag gca ggg atg gcg gcc gtc gca gac ccc cac agc 1857 Gly Val Glu Gly LysAla Gly Met Ala Ala Val Ala Asp Pro His Ser 550 555 560 ctg ctg gac cccaac gcg ata tac cag gag ctg cag aag gtg ctg gca 1905 Leu Leu Asp Pro AsnAla Ile Tyr Gln Glu Leu Gln Lys Val Leu Ala 565 570 575 ccc tat gcc cggccc atc ttc ctg cgc ctc ctg ccc cag gtg gac acc 1953 Pro Tyr Ala Arg ProIle Phe Leu Arg Leu Leu Pro Gln Val Asp Thr 580 585 590 aca ggc acc ttcaag atc cag aag acg agg ctg cag cga gag ggc ttt 2001 Thr Gly Thr Phe LysIle Gln Lys Thr Arg Leu Gln Arg Glu Gly Phe 595 600 605 gac cca cgc cagacc tca gac cgg ctc ttc ttc ctg gac ctg aag cag 2049 Asp Pro Arg Gln ThrSer Asp Arg Leu Phe Phe Leu Asp Leu Lys Gln 610 615 620 625 ggc cac tacctg ccc tta aat gag gca gtc tac act cgc atc tgc tcg 2097 Gly His Tyr LeuPro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys Ser 630 635 640 ggc gcc ttcgcc ctc tgaagctgtt cctctactgg ccacaaactc tgggcctggt 2152 Gly Ala Phe AlaLeu 645 gggagaggcc agcttgagcc agacagcgct gcccaggggt ggccgcctagtacacaccca 2212 cctggccgag ctgtacctgg cacggcccat cctggactga gaaactggaacctcagagga 2272 acccgtgcct ctctgctgcc ttggtgcccc tgtgtctgcc tcctctccctgcttttcagc 2332 ctctgtctcc ttccatccct gtccctgtct ggccttaact cttccctctctttcttttct 2392 ttctttcttt cttttttttt aagatagagt ctcactctgc tgcccgggctagagtgcagt 2452 ggtgggatct cggctcactg caacctctgc ctcctggggt tcaagtgatcctcccacctc 2512 agcctcctga gtagctggga ttacaggcac ccgccaccac gtccagctaatttttatatt 2572 tttagtagag acggggtttc accatgttgg tcaggctggt cttgaactcctgacctcagg 2632 tgatccgctg gcctcggcct cccagagtgc tgggattata ggcgtgagcctctggcccgg 2692 cctttccttt ttcctctcct ctcctgccga gagtggaaca cacgtgtcctgggagctgca 2752 tcttgtgtag ggtccagctg cttttgggga ctgcaggaat catctcccctgggccctgga 2812 ctcggactgg ggcctcccca cctccctctc ggctgtgcct tacggagccccaatccaggc 2872 ctcctgtggc tgttgggttc cagatgctgc agctccatgt gacttccaagcaggccctcc 2932 gccctccctg ctgaatggag gagccggggg tcccccaggc caactggaaaatctcccagg 2992 ctaggccaat tgccttttgc acttccccgt tcctgtcaca tttccccagccccaccttcc 3052 cctcctgatg ccctgaaagc ttccggaatt gactgtgacc acttggatgtcaccactgtc 3112 agcccctgcc ttgatgtccc catttagcca tctccatgga gctcctgctggagggccctg 3172 aaccctgcac tgcgtggctg cccagccagc tgcctcctgt cctgggaggaggcctcctgg 3232 gtgtcctcat ctggtgtgtc tactggaggg tcccacagga gaggcagcagaggggtcagg 3292 ggaggtctcc tgccgggggt tggcctctca agcctcaggg gttctagcctgttgaatata 3352 ccccacctgg tgggtggccc ctccgatgtc cccactgatg gctctgacaccgtgttggtg 3412 gcgatgtccc agacaatccc accaggacgg cccagacatc cctactggcttcgctggtgg 3472 ctcatctcga acatccacgc cagcctttct ggggccggcc acccaggccgcctgtccgtc 3532 tgtcctccct ccagcagcac cccctggccc ctggagtggt ggggccatggcaagagacac 3592 cgtggcgtct catgtgaact ttcctgggca ctgtggtttt atttcctaattgatttaaga 3652 aataaacctg aagaccgtct ggtgaaaaaa aaaaaaaaaa aagggcggccgc 3704 25 646 PRT Homo sapiens 25 Met Arg Ala Pro Gly Ala Gly Ala AlaSer Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro TrpThr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr Val Gly Ser Gly GlyTrp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu PheGly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His GlnArg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Val GlnArg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Gly Thr Gly Glu CysTrp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser Asn Ala Val Ala AsnLeu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala IlePhe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly LeuAla Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150 155 160 Asn LeuArg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala 165 170 175 LysAla Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala Glu Val 180 185 190Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser Gly Asp Leu 195 200205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu Asp Pro Leu Leu 210215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile Pro Ser Lys Gly Met225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr GlyLeu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg MetAla Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met Gln Ala Ala Asp ValLeu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile IleGly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu Thr Val Val Leu ArgLys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Ile LysTyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg TyrLeu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu Arg Arg His Arg ValArg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu GluPhe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr GlyAla Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly LysVal Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val 405 410 415 TyrPro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Leu Leu 420 425 430Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly Glu Pro Gly 435 440445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys Ile Ala His Ser Val465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val LeuVal Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser GlyAsp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu ValGlu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala ValTyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly Met AlaAla Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu Asp Pro Asn Ala IleTyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro Tyr Ala Arg Pro IlePhe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe LysIle Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg GlnThr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly His TyrLeu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630 635 640 Ser GlyAla Phe Ala Leu 645 26 2917 DNA Homo sapiens CDS (208)...(2136) 26cgacccacgc gtccgggcgg gcggggccgg gcggcgggcg gggctggcgg ggcggccggg 60ccatgcaggg cgcagagccg gctaaaccct gctgagaccc ggctccgtgc gtccaggggc 120ggctaatgcc cctcacgctg tctacgctgc tgcaaccggg ccgcatctgg acggggcgcc 180gcgcggcgga gccgacgccg ggccaca atg ctg ctt gga gcc tct ctg gtg ggg 234Met Leu Leu Gly Ala Ser Leu Val Gly 1 5 gtg ctg ctg ttc tcc aag ctg gtgctg aaa ctg ccc tgg acc cag gtg 282 Val Leu Leu Phe Ser Lys Leu Val LeuLys Leu Pro Trp Thr Gln Val 10 15 20 25 gga ttc tcc ctg ttg ttc ctc tacttg gga tct ggc ggc tgg cgc ttc 330 Gly Phe Ser Leu Leu Phe Leu Tyr LeuGly Ser Gly Gly Trp Arg Phe 30 35 40 atc cgg gtc ttc atc aag acc atc aggcgc gat atc ttt ggc ggc ctg 378 Ile Arg Val Phe Ile Lys Thr Ile Arg ArgAsp Ile Phe Gly Gly Leu 45 50 55 gtc ctc ctg aag gtg aag gca aag gtg cgacag tgc ctg cag gag cgg 426 Val Leu Leu Lys Val Lys Ala Lys Val Arg GlnCys Leu Gln Glu Arg 60 65 70 cgg aca gtg ccc att ttg ttt gcc tct acc gttcgg cgc cac ccc gac 474 Arg Thr Val Pro Ile Leu Phe Ala Ser Thr Val ArgArg His Pro Asp 75 80 85 aag acg gcc ctg atc ttc gag ggc aca gat acc cactgg acc ttc cgc 522 Lys Thr Ala Leu Ile Phe Glu Gly Thr Asp Thr His TrpThr Phe Arg 90 95 100 105 cag ctg gat gag tac tca agc agt gta gcc aacttc ctg cag gcc cgg 570 Gln Leu Asp Glu Tyr Ser Ser Ser Val Ala Asn PheLeu Gln Ala Arg 110 115 120 ggc ctg gcc tcg ggc gat gtg gct gcc atc ttcatg gag aac cgc aat 618 Gly Leu Ala Ser Gly Asp Val Ala Ala Ile Phe MetGlu Asn Arg Asn 125 130 135 gag ttc gtg ggc cta tgg ctg ggc atg gcc aagctc ggt gtg gag gca 666 Glu Phe Val Gly Leu Trp Leu Gly Met Ala Lys LeuGly Val Glu Ala 140 145 150 gcc ctc atc aac acc aac ctg cgg cgg gat gctctg ctc cac tgc ctc 714 Ala Leu Ile Asn Thr Asn Leu Arg Arg Asp Ala LeuLeu His Cys Leu 155 160 165 acc acc tcg cgc gca cgg gcc ctt gtc ttt ggcagc gaa atg gcc tca 762 Thr Thr Ser Arg Ala Arg Ala Leu Val Phe Gly SerGlu Met Ala Ser 170 175 180 185 gcc atc tgt gag gtc cat gcc agc ctg gacccc tcg ctc agc ctc ttc 810 Ala Ile Cys Glu Val His Ala Ser Leu Asp ProSer Leu Ser Leu Phe 190 195 200 tgc tct ggc tcc tgg gag ccc ggt gcg gtgcct cca agc aca gaa cac 858 Cys Ser Gly Ser Trp Glu Pro Gly Ala Val ProPro Ser Thr Glu His 205 210 215 ctg gac cct ctg ctg aaa gat gct ccc aagcac ctt ccc agt tgc cct 906 Leu Asp Pro Leu Leu Lys Asp Ala Pro Lys HisLeu Pro Ser Cys Pro 220 225 230 gac aag ggc ttc aca gat aaa ctg ttc tacatc tac aca tcc ggc acc 954 Asp Lys Gly Phe Thr Asp Lys Leu Phe Tyr IleTyr Thr Ser Gly Thr 235 240 245 aca ggg ctg ccc aag gcc gcc atc gtg gtgcac agc agg tat tac cgc 1002 Thr Gly Leu Pro Lys Ala Ala Ile Val Val HisSer Arg Tyr Tyr Arg 250 255 260 265 atg gct gcc ctg gtg tac tat gga ttccgc atg cgg ccc aac gac atc 1050 Met Ala Ala Leu Val Tyr Tyr Gly Phe ArgMet Arg Pro Asn Asp Ile 270 275 280 gtc tat gac tgc ctc ccc ctc tac cactca gca gga aac atc gtg gga 1098 Val Tyr Asp Cys Leu Pro Leu Tyr His SerAla Gly Asn Ile Val Gly 285 290 295 atc ggc cag tgc ctg ctg cat ggc atgacg gtg gtg att cgg aag aag 1146 Ile Gly Gln Cys Leu Leu His Gly Met ThrVal Val Ile Arg Lys Lys 300 305 310 ttc tca gcc tcc cgg ttc tgg gac gattgt atc aag tac aac tgc acg 1194 Phe Ser Ala Ser Arg Phe Trp Asp Asp CysIle Lys Tyr Asn Cys Thr 315 320 325 att gtg cag tac att ggt gaa ctg tgccgc tac ctc ctg aac cag cca 1242 Ile Val Gln Tyr Ile Gly Glu Leu Cys ArgTyr Leu Leu Asn Gln Pro 330 335 340 345 ccg cgg gag gca gaa aac cag caccag gtt cgc atg gca cta ggc aat 1290 Pro Arg Glu Ala Glu Asn Gln His GlnVal Arg Met Ala Leu Gly Asn 350 355 360 ggc ctc cgg cag tcc atc tgg accaac ttt tcc agc cgc ttc cac ata 1338 Gly Leu Arg Gln Ser Ile Trp Thr AsnPhe Ser Ser Arg Phe His Ile 365 370 375 ccc cag gtg gct gag ttc tac ggggcc aca gag tgc aac tgt agc ctg 1386 Pro Gln Val Ala Glu Phe Tyr Gly AlaThr Glu Cys Asn Cys Ser Leu 380 385 390 ggc aac ttc gac agc cag gtg ggggcc tgt ggt ttc aat agc cgc atc 1434 Gly Asn Phe Asp Ser Gln Val Gly AlaCys Gly Phe Asn Ser Arg Ile 395 400 405 ctg tcc ttc gtg tac ccc atc cggttg gta cgt gtc aac gag gac acc 1482 Leu Ser Phe Val Tyr Pro Ile Arg LeuVal Arg Val Asn Glu Asp Thr 410 415 420 425 atg gag ctg atc cgg ggg cccgac ggc gtc tgc att ccc tgc cag cca 1530 Met Glu Leu Ile Arg Gly Pro AspGly Val Cys Ile Pro Cys Gln Pro 430 435 440 ggt gag ccg ggc cag ctg gtgggc cgc atc atc cag aaa gac ccc ctg 1578 Gly Glu Pro Gly Gln Leu Val GlyArg Ile Ile Gln Lys Asp Pro Leu 445 450 455 cgc cgc ttc gat ggc tac ctcaac cag ggc gcc aac aac aag aag att 1626 Arg Arg Phe Asp Gly Tyr Leu AsnGln Gly Ala Asn Asn Lys Lys Ile 460 465 470 gcc aag gat gtc ttc aag aagggg gac cag gcc tac ctt act ggt gat 1674 Ala Lys Asp Val Phe Lys Lys GlyAsp Gln Ala Tyr Leu Thr Gly Asp 475 480 485 gtg ctg gtg atg gac gag ctgggc tac ctg tac ttc cga gac cgc act 1722 Val Leu Val Met Asp Glu Leu GlyTyr Leu Tyr Phe Arg Asp Arg Thr 490 495 500 505 ggg gac acg ttc cgc tggaaa ggt gag aac gtg tcc acc acc gag gtg 1770 Gly Asp Thr Phe Arg Trp LysGly Glu Asn Val Ser Thr Thr Glu Val 510 515 520 gaa ggc aca ctc agc cgcctg ctg gac atg gct gac gtg gcc gtg tat 1818 Glu Gly Thr Leu Ser Arg LeuLeu Asp Met Ala Asp Val Ala Val Tyr 525 530 535 ggt gtc gag gtg cca ggaacc gag ggc cgg gcc gga atg gct gct gtg 1866 Gly Val Glu Val Pro Gly ThrGlu Gly Arg Ala Gly Met Ala Ala Val 540 545 550 gcc agc ccc act ggc aactgt gac ctg gag cgc ttt gct cag gtc ttg 1914 Ala Ser Pro Thr Gly Asn CysAsp Leu Glu Arg Phe Ala Gln Val Leu 555 560 565 gag aag gaa ctg ccc ctgtat gcg cgc ccc atc ttc ctg cgc ctc ctg 1962 Glu Lys Glu Leu Pro Leu TyrAla Arg Pro Ile Phe Leu Arg Leu Leu 570 575 580 585 cct gag ctg cac aaaaca gga acc tac aag ttc cag aag aca gag cta 2010 Pro Glu Leu His Lys ThrGly Thr Tyr Lys Phe Gln Lys Thr Glu Leu 590 595 600 cgg aag gag ggc tttgac ccg gct att gtg aaa gac ccg ctg ttc tat 2058 Arg Lys Glu Gly Phe AspPro Ala Ile Val Lys Asp Pro Leu Phe Tyr 605 610 615 cta gat gcc cag aagggc cgc tac gtc ccg ctg gac caa gag gcc tac 2106 Leu Asp Ala Gln Lys GlyArg Tyr Val Pro Leu Asp Gln Glu Ala Tyr 620 625 630 agc cgc atc cag gcaggc gag gag aag ctg tgattccccc catccctctg 2156 Ser Arg Ile Gln Ala GlyGlu Glu Lys Leu 635 640 agggccggcg gatgctggat ccggagcccc aggttccgccccagagcggt cctggacaag 2216 gccagaccaa agcaagcagg gcctggcacc tccatcctgaggtgctgccc ctccatccaa 2276 aactgccaag tgactcattg ccttcccaac ccttccagaggctttctgtg aaagtctcat 2336 gtccaagttc cgtcttctgg gctgggcagg ccctctggttcccaggctga gactgacggg 2396 ttttctcagg atgatgtctt gggtgagggt agggagaggacaaggggtca ccgagccctt 2456 cccagagagc agggagctta taaatggaac cagagcagaagtccccagac tcaggaagtc 2516 aacagagtgg gcagggacag tggtagcatc catctggtggccaaagagaa tcgtagcccc 2576 agagctgccc aagttcactg ggctccaccc ccacctccaggaggggagga gaggacctga 2636 catctgtagg tggcccctga tgccccatct acagcaggaggtcaggacca cgcccctggc 2696 ctctccccac tcccccatcc tcctccctgg gtggctgcctgattatccct caggcagggc 2756 ctctcagtcc ttgtgggtct gtgtcacctc catctcagtcttggcctggc tatgagggga 2816 ggaggaatgg gagagggggc tcaggggcca ataaactctgccttgagtcc tcctaaaaaa 2876 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa agggcggccg c2917 27 643 PRT Homo sapiens 27 Met Leu Leu Gly Ala Ser Leu Val Gly ValLeu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln ValGly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg PheIle Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly LeuVal Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu ArgArg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His ProAsp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr PheArg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu GlnAla Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met GluAsn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys LeuGly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg AspAla Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu ValPhe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 SerLeu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys AlaAla 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu ValTyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp CysLeu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly GlnCys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe SerAla Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys ThrIle Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn GlnPro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala LeuGly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser ArgPhe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu CysAsn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala CysGly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg LeuVal Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 AspGly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp GluLeu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe ArgTrp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr LeuSer Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val GluVal Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala SerPro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val LeuGlu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg LeuLeu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys ThrGlu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp ProLeu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu AspGln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu28 1941 DNA Homo sapiens 28 atgcgggctc cgggtgcggg cgcggcctcg gtggtctcgctggcgctgtt gtggctgctg 60 gggctgccgt ggacctggag cgcggcagcg gcgctcggcgtgtacgtggg cagcggcggc 120 tggcgcttcc tgcgcatcgt ctgcaagacc gcgaggcgagacctcttcgg tctctctgtg 180 ctgatccgcg tgcgcctgga gctgcggcgg caccagcgtgccggccacac catcccgcgc 240 atctttcagg cggtagtgca gcgacagccc gagcgcctggcgctggtgga tgccgggacc 300 ggcgagtgct ggacctttgc gcagctggac gcctactccaatgcggtagc caacctcttc 360 cgccagctgg gcttcgcgcc gggcgacgtg gtggccatcttcctggaggg ccggccggag 420 ttcgtggggc tgtggctggg cctggccaag gcgggcatggaggccgcgct gctcaacgtg 480 aacctgcggc gcgagcccct ggccttctgc ctgggcacctcgggcgctaa ggccctgatc 540 tttggaggag aaatggtggc ggcggtggcc gaagtgagcgggcatctggg gaaaagtttg 600 atcaagttct gctctggaga cttggggccc gagggcatcttgccggacac ccacctcctg 660 gacccgctgc tgaaggaggc ctctactgcc cccttggcacagatccccag caagggcatg 720 gacgatcgtc ttttctacat ctacacgtcg gggaccaccgggctgcccaa ggctgccatt 780 gtcgtgcaca gcaggtacta ccgcatggca gccttcggccaccacgccta ccgcatgcag 840 gcggctgacg tgctctatga ctgcctgccc ctgtaccactcggcaggaaa catcatcggc 900 gtggggcagt gtctcatcta tgggctgaca gtcgtcctccgcaagaaatt ctcggccagc 960 cgcttctggg acgactgcat caagtacaac tgcacggtggttcagtacat cggggagatc 1020 tgccgctacc tgctgaagca gccggtgcgc gaggcggagaggcgacaccg cgtgcgcctg 1080 gcggtgggga acgggctgcg tcctgccatc tgggaggagttcacggagcg cttcggcgta 1140 cgccaaatcg gggagttcta cggcgccacc gagtgcaactgcagcattgc caacatggac 1200 ggcaaggtcg gctcctgtgg tttcaacagc cgcatcctgccccacgtgta ccccatccgg 1260 ctggtgaagg tcaatgagga cacaatggag ctgctgcgggatgcccaggg cctctgcatc 1320 ccctgccagg ccggggagcc tggcctcctt gtgggtcagatcaaccaaca ggacccgctg 1380 cgccgcttcg atggctatgt cagcgagagc gccaccagcaagaagatcgc ccacagcgtc 1440 ttcagcaagg gcgacagcgc ctacctctca ggtgacgtgctagtgatgga tgagctgggc 1500 tacatgtact tccgggaccg tagcggggac accttccgctggcgagggga gaacgtctcc 1560 accaccgagg tggagggcgt gctgagccgc ctgctgggccagacagacgt ggccgtctat 1620 ggggtggctg ttccaggagt ggagggtaag gcagggatggcggccgtcgc agacccccac 1680 agcctgctgg accccaacgc gatataccag gagctgcagaaggtgctggc accctatgcc 1740 cggcccatct tcctgcgcct cctgccccag gtggacaccacaggcacctt caagatccag 1800 aagacgaggc tgcagcgaga gggctttgac ccacgccagacctcagaccg gctcttcttc 1860 ctggacctga agcagggcca ctacctgccc ttaaatgaggcagtctacac tcgcatctgc 1920 tcgggcgcct tcgccctctg a 1941 29 1938 DNA Musmusculus 29 atgcgggctc ctggagcagg aacagcctct gtggcctcac tggcgctgctttggtttctg 60 ggacttccgt ggacctggag cgcggcggcg gcgttctgtg tgtacgtgggtggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacg gcgaggcgag acctctttggcctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacga caccggcgag caggagacacgatcccgtgc 240 atcttccagg ctgtggcccg gcgacaacca gagcgcctgg cactggtggacgccagtagt 300 ggtatatgct ggaccttcgc acagctggac acctactcca atgctgtagccaacctgttc 360 cgccagctgg gctttgcacc aggcgatgtg gtggctgtgt tcctggagggccggccggag 420 ttcgtgggac tgtggctggg cctggccaag gccggtgtgg tggctgctcttctcaatgtc 480 aacctgaggc gggagcccct ggccttctgc ctgggcacat cagctgccaaggccctcatt 540 tatggcgggg agatggcagc ggcggtggcg gaggtgagcg agcagctggggaagagcctc 600 ctcaagttct gctctggaga tctggggcct gagagcatcc tgcctgacacgcagctcctg 660 gaccccatgc ttgctgaggc gcccaccaca cccctggcac aagccccaggcaagggcatg 720 gatgatcggc tgttttacat ctatacttct gggaccaccg ggcttcctaaggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgct gcctttggcc accattcctacagcatgcgt 840 gccgccgatg tgctctatga ctgcctgcca ctctaccact ctgcagggaacatcatgggt 900 gtggggcagt gcgtcatcta cgggttgacg gtggtactgc gcaagaagttctccgccagc 960 cgcttctggg atgactgtgt caagtacaat tgcacggtag tgcagtacataggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgc gacgtggagc agcgacaccgcgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatc tgggaggagt tcacgcagcgcttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctacc gagtgcaact gcagcattgccaacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagc cgtatcctca cgcatgtgtaccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggag ccactgcggg actccgagggcctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctc gtgggccaga tcaaccagcaggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagt gccaccaaca agaagattgcccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctca ggtgacgtgc tagtgatggacgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggac accttccgct ggcgcggggagaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgc ctactgggcc agacggacgtggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaa gctggcatgg cagccatcgcagatccccac 1680 agccagttgg accctaactc aatgtaccag gaattacaga aggttcttgcatcctatgct 1740 cggcccatct tcctgcgtct tctgccccag gtggatacca caggcaccttcaagatccag 1800 aagacccggc tgcagcgtga aggctttgac ccccgtcaga cctcagacaggctcttcttt 1860 ctagacctga agcagggacg ctatgtaccc ctggatgaga gagtccatgcccgcatttgt 1920 gcaggcgact tctcactc 1938 30 1896 DNA Homo sapiens 30ctgttctcca agctggtgct gaaactgccc tggacccagg tgggattctc cctgttgttc 60ctctacttgg gatctggcgg ctggcgcttc atccgggtct tcatcaagac catcaggcgc 120gatatctttg gcggcctggt cctcctgaag gtgaaggcaa aggtgcgaca gtgcctgcag 180gagcggcgga cagtgcccat tttgtttgcc tctaccgttc ggcgccaccc cgacaagacg 240gccctgatct tcgagggcac agatacccac tggaccttcc gccagctgga tgagtactca 300agcagtgtag ccaacttcct gcaggcccgg ggcctggcct cgggcgatgt ggctgccatc 360ttcatggaga accgcaatga gttcgtgggc ctatggctgg gcatggccaa gctcggtgtg 420gaggcagccc tcatcaacac caacctgcgg cgggatgctc tgctccactg cctcaccacc 480tcgcgcgcac gggcccttgt ctttggcagc gaaatggcct cagccatctg tgaggtccat 540gccagcctgg acccctcgct cagcctcttc tgctctggct cctgggagcc cggtgcggtg 600cctccaagca cagaacacct ggaccctctg ctgaaagatg ctcccaagca ccttcccagt 660tgccctgaca agggcttcac agataaactg ttctacatct acacatccgg caccacaggg 720ctgcccaagg ccgccatcgt ggtgcacagc aggtattacc gcatggctgc cctggtgtac 780tatggattcc gcatgcggcc caacgacatc gtctatgact gcctccccct ctaccactca 840gcaggaaaca tcgtgggaat cggccagtgc ctgctgcatg gcatgacggt ggtgattcgg 900aagaagttct cagcctcccg gttctgggac gattgtatca agtacaactg cacgattgtg 960cagtacattg gtgaactgtg ccgctacctc ctgaaccagc caccgcggga ggcagaaaac 1020cagcaccagg ttcgcatggc actaggcaat ggcctccggc agtccatctg gaccaacttt 1080tccagccgct tccacatacc ccaggtggct gagttctacg gggccacaga gtgcaactgt 1140agcctgggca acttcgacag ccaggtgggg gcctgtggtt tcaatagccg catcctgtcc 1200ttcgtgtacc ccatccggtt ggtacgtgtc aacgaggaca ccatggagct gatccggggg 1260cccgacggcg tctgcattcc ctgccagcca ggtgagccgg gccagctggt gggccgcatc 1320atccagaaag accccctgcg ccgcttcgat ggctacctca accagggcgc caacaacaag 1380aagattgcca aggatgtctt caagaagggg gaccaggcct accttactgg tgatgtgctg 1440gtgatggacg agctgggcta cctgtacttc cgagaccgca ctggggacac gttccgctgg 1500aaaggtgaga acgtgtccac caccgaggtg gaaggcacac tcagccgcct gctggacatg 1560gctgacgtgg ccgtgtatgg tgtcgaggtg ccaggaaccg agggccgggc cggaatggct 1620gctgtggcca gccccactgg caactgtgac ctggagcgct ttgctcaggt cttggagaag 1680gaactgcccc tgtatgcgcg ccccatcttc ctgcgcctcc tgcctgagct gcacaaaaca 1740ggaacctaca agttccagaa gacagagcta cggaaggagg gctttgaccc ggctattgtg 1800aaagacccgc tgttctatct agatgcccag aagggccgct acgtcccgct ggaccaagag 1860gcctacagcc gcatccaggc aggcgaggag aagctg 1896 31 1896 DNA Mus musculus 31cttgggtcca agctagtgct gaagctgccc tggacccagg tgggattctc cctgttgctc 60ctgtacttgg ggtctggtgg ctggcgtttc atccgggtct tcatcaagac ggtcaggaga 120gatatctttg gtggcatggt gctcctgaag gtgaagacca aggtgcgacg gtaccttcag 180gagcggaaga cggtgcccct gctgtttgct tcaatggtac agcgccaccc ggacaagaca 240gccctgattt tcgagggcac agacactcac tggaccttcc gccagctgga tgagtactcc 300agtagtgtgg ccaacttcct gcaggcccgg ggcctggcct caggcaatgt agttgccctc 360tttatggaaa accgcaatga gtttgtgggt ctgtggctag gcatggccaa gctgggcgtg 420gaggcggctc tcatcaacac caaccttagg cgggatgccc tgcgccactg tcttgacacc 480tcaaaggcac gagctctcat ctttggcagt gagatggcct cagctatctg tgagatccat 540gctagcctgg agcccacact cagcctcttc tgctctggat cctgggagcc cagcacagtg 600cccgtcagca cagagcatct ggaccctctt ctggaagatg ccccgaagca cctgcccagt 660cacccagaca agggttttac agataagctc ttctacatct acacatcggg caccacgggg 720ctacccaaag ctgccattgt ggtgcacagc aggtattatc gtatggcttc cctggtgtac 780tatggattcc gcatgcggcc tgatgacatt gtctatgact gcctccccct ctaccactca 840agcaggaaac atcgtgggga ttggcagtgc ttactccacg gcatgactgt ggtgatccgg 900aagaagttct cagcctcccg gttctgggat gattgtatca agtacaactg cacagtggta 960cagtacattg gcgagctctg ccgctacctc ctgaaccagc caccccgtga ggctgagtct 1020cggcacaagg tgcgcatggc actgggcaac ggtctccggc agtccatctg gaccgacttc 1080tccagccgtt tccacatccc ccaggtggct gagttctatg gggccactga atgcaactgt 1140agcctgggca actttgacag ccgggtgggg gcctgtggct tcaatagccg catcctgtcc 1200tttgtgtacc ctatccgttt ggtacgtgtc aatgaggata ccatggaact gatccgggga 1260cccgatggag tctgcattcc ctgtcaacca ggtcagccag gccagctggt gggtcgcatc 1320atccagcagg accctctgcg ccgtttcgac gggtacctca accagggtgc caacaacaag 1380aagattgcta atgatgtctt caagaagggg gaccaagcct acctcactgg tgacgtcctg 1440gtgatggatg agctgggtta cctgtacttc cgagatcgca ctggggacac gttccgctgg 1500aaaggggaga atgtatctac cactgaggtg gagggcacac tcagccgcct gcttcatatg 1560gcagatgtgg cagtttatgg tgttgaggtg ccaggaactg aaggccgagc aggaatggct 1620gccgttgcaa gtcccatcag caactgtgac ctggagagct ttgcacagac cttgaaaaag 1680gagctgcctc tgtatgcccg ccccatcttc ctgcgcttct tgcctgagct gcacaagaca 1740gggaccttca agttccagaa gacagagttg cggaaggagg gctttgaccc atctgttgtg 1800aaagacccgc tgttctatct ggatgctcgg aagggctgct acgttgcact ggaccaggag 1860gcctataccc gcatccaggc aggcgaggag aagctg 1896 32 646 PRT Homo sapiens 32Met Arg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 1015 Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 2530 Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 4045 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 5560 Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 7075 80 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 8590 95 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala ProGly 115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe ValGly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala LeuLeu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys LeuGly Thr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met ValAla Ala Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu IleLys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro AspThr His Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala ProLeu Ala Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu PheTyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala IleVal Val His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His HisAla Tyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu ProLeu Tyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 LeuIle Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315320 Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala340 345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu ArgPro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg GlnIle Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile AlaAsn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser ArgIle Leu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn GluAsp Thr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile ProCys Gln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn GlnGln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser AlaThr Ser Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly AspSer Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu GlyTyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp ArgGly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser ArgLeu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 ProGly Val Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555560 Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565570 575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg GluGly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu AspLeu Lys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr ThrArg Ile Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 33 646 PRT Musmusculus 33 Met Arg Ala Pro Gly Ala Gly Thr Ala Ser Val Ala Ser Leu AlaLeu 1 5 10 15 Leu Trp Phe Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala AlaAla Phe 20 25 30 Cys Val Tyr Val Gly Gly Gly Gly Trp Arg Phe Leu Arg IleVal Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu IleArg Val 50 55 60 Arg Leu Glu Leu Arg Arg His Arg Arg Ala Gly Asp Thr IlePro Cys 65 70 75 80 Ile Phe Gln Ala Val Ala Arg Arg Gln Pro Glu Arg LeuAla Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile Cys Trp Thr Phe Ala Gln LeuAsp Thr Tyr 100 105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu GlyPhe Ala Pro Gly 115 120 125 Asp Val Val Ala Val Phe Leu Glu Gly Arg ProGlu Phe Val Gly Leu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Val ValAla Ala Leu Leu Asn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu AlaPhe Cys Leu Gly Thr Ser Ala Ala 165 170 175 Lys Ala Leu Ile Tyr Gly GlyGlu Met Ala Ala Ala Val Ala Glu Val 180 185 190 Ser Glu Gln Leu Gly LysSer Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Ser IleLeu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210 215 220 Ala Glu Ala ProThr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met 225 230 235 240 Asp AspArg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 LysAla Ala Ile Val Val His Ser Arg Tyr Tyr Arg Ile Ala Ala Phe 260 265 270Gly His His Ser Tyr Ser Met Arg Ala Ala Asp Val Leu Tyr Asp Cys 275 280285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Met Gly Val Gly Gln Cys 290295 300 Val Ile Tyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser305 310 315 320 Arg Phe Trp Asp Asp Cys Val Lys Tyr Asn Cys Thr Val ValGln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Arg Gln Pro ValArg Asp Val 340 345 350 Glu Gln Arg His Arg Val Arg Leu Ala Val Gly AsnGly Leu Arg Pro 355 360 365 Ala Ile Trp Glu Glu Phe Thr Gln Arg Phe GlyVal Pro Gln Ile Gly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn CysSer Ile Ala Asn Met Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly PheAsn Ser Arg Ile Leu Thr His Val 405 410 415 Tyr Pro Ile Arg Leu Val LysVal Asn Glu Asp Thr Met Glu Pro Leu 420 425 430 Arg Asp Ser Glu Gly LeuCys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly GlnIle Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val SerAsp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe ArgLys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 AspGlu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Val Leu 515 520525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530535 540 Pro Gly Val Glu Gly Lys Ala Gly Met Ala Ala Ile Ala Asp Pro His545 550 555 560 Ser Gln Leu Asp Pro Asn Ser Met Tyr Gln Glu Leu Gln LysVal Leu 565 570 575 Ala Ser Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu ProGln Val Asp 580 585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg LeuGln Arg Glu Gly 595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu PhePhe Leu Asp Leu Lys 610 615 620 Gln Gly Arg Tyr Val Pro Leu Asp Glu ArgVal His Ala Arg Ile Cys 625 630 635 640 Ala Gly Asp Phe Ser Leu 645 34632 PRT Homo sapiens 34 Leu Phe Ser Lys Leu Val Leu Lys Leu Pro Trp ThrGln Val Gly Phe 1 5 10 15 Ser Leu Leu Phe Leu Tyr Leu Gly Ser Gly GlyTrp Arg Phe Ile Arg 20 25 30 Val Phe Ile Lys Thr Ile Arg Arg Asp Ile PheGly Gly Leu Val Leu 35 40 45 Leu Lys Val Lys Ala Lys Val Arg Gln Cys LeuGln Glu Arg Arg Thr 50 55 60 Val Pro Ile Leu Phe Ala Ser Thr Val Arg ArgHis Pro Asp Lys Thr 65 70 75 80 Ala Leu Ile Phe Glu Gly Thr Asp Thr HisTrp Thr Phe Arg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser Ser Val Ala Asn PheLeu Gln Ala Arg Gly Leu 100 105 110 Ala Ser Gly Asp Val Ala Ala Ile PheMet Glu Asn Arg Asn Glu Phe 115 120 125 Val Gly Leu Trp Leu Gly Met AlaLys Leu Gly Val Glu Ala Ala Leu 130 135 140 Ile Asn Thr Asn Leu Arg ArgAsp Ala Leu Leu His Cys Leu Thr Thr 145 150 155 160 Ser Arg Ala Arg AlaLeu Val Phe Gly Ser Glu Met Ala Ser Ala Ile 165 170 175 Cys Glu Val HisAla Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser 180 185 190 Gly Ser TrpGlu Pro Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp 195 200 205 Pro LeuLeu Lys Asp Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys 210 215 220 GlyPhe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 225 230 235240 Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala 245250 255 Ala Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr260 265 270 Asp Cys Leu Pro Leu Tyr His Ser Ala Gly Asn Ile Val Gly IleGly 275 280 285 Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys LysPhe Ser 290 295 300 Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn CysThr Ile Val 305 310 315 320 Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu LeuAsn Gln Pro Pro Arg 325 330 335 Glu Ala Glu Asn Gln His Gln Val Arg MetAla Leu Gly Asn Gly Leu 340 345 350 Arg Gln Ser Ile Trp Thr Asn Phe SerSer Arg Phe His Ile Pro Gln 355 360 365 Val Ala Glu Phe Tyr Gly Ala ThrGlu Cys Asn Cys Ser Leu Gly Asn 370 375 380 Phe Asp Ser Gln Val Gly AlaCys Gly Phe Asn Ser Arg Ile Leu Ser 385 390 395 400 Phe Val Tyr Pro IleArg Leu Val Arg Val Asn Glu Asp Thr Met Glu 405 410 415 Leu Ile Arg GlyPro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu 420 425 430 Pro Gly GlnLeu Val Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg 435 440 445 Phe AspGly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys 450 455 460 AspVal Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu 465 470 475480 Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp 485490 495 Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly500 505 510 Thr Leu Ser Arg Leu Leu Asp Met Ala Asp Val Ala Val Tyr GlyVal 515 520 525 Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala ValAla Ser 530 535 540 Pro Thr Gly Asn Cys Asp Leu Glu Arg Phe Ala Gln ValLeu Glu Lys 545 550 555 560 Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe LeuArg Leu Leu Pro Glu 565 570 575 Leu His Lys Thr Gly Thr Tyr Lys Phe GlnLys Thr Glu Leu Arg Lys 580 585 590 Glu Gly Phe Asp Pro Ala Ile Val LysAsp Pro Leu Phe Tyr Leu Asp 595 600 605 Ala Gln Lys Gly Arg Tyr Val ProLeu Asp Gln Glu Ala Tyr Ser Arg 610 615 620 Ile Gln Ala Gly Glu Glu LysLeu 625 630 35 632 PRT Mus musculus 35 Leu Gly Ser Lys Leu Val Leu LysLeu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 Ser Leu Leu Leu Leu Tyr LeuGly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 Val Phe Ile Lys Thr Val ArgArg Asp Ile Phe Gly Gly Met Val Leu 35 40 45 Leu Lys Val Lys Thr Lys ValArg Arg Tyr Leu Gln Glu Arg Lys Thr 50 55 60 Val Pro Leu Leu Phe Ala SerMet Val Gln Arg His Pro Asp Lys Thr 65 70 75 80 Ala Leu Ile Phe Glu GlyThr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95 Asp Glu Tyr Ser Ser SerVal Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105 110 Ala Ser Gly Asn ValVal Ala Leu Phe Met Glu Asn Arg Asn Glu Phe 115 120 125 Val Gly Leu TrpLeu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu 130 135 140 Ile Asn ThrAsn Leu Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr 145 150 155 160 SerLys Ala Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile 165 170 175Cys Glu Ile His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser 180 185190 Gly Ser Trp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His Leu Asp 195200 205 Pro Leu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro Asp Lys210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr ThrGly 225 230 235 240 Leu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr TyrArg Met Ala 245 250 255 Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro AspAsp Ile Val Tyr 260 265 270 Asp Cys Leu Pro Leu Tyr His Ser Ser Arg LysHis Arg Gly Asp Trp 275 280 285 Gln Cys Leu Leu His Gly Met Thr Val ValIle Arg Lys Lys Phe Ser 290 295 300 Ala Ser Arg Phe Trp Asp Asp Cys IleLys Tyr Asn Cys Thr Val Val 305 310 315 320 Gln Tyr Ile Gly Glu Leu CysArg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335 Glu Ala Glu Ser Arg HisLys Val Arg Met Ala Leu Gly Asn Gly Leu 340 345 350 Arg Gln Ser Ile TrpThr Asp Phe Ser Ser Arg Phe His Ile Pro Gln 355 360 365 Val Ala Glu PheTyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn 370 375 380 Phe Asp SerArg Val Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser 385 390 395 400 PheVal Tyr Pro Ile Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu 405 410 415Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln 420 425430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg 435440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Asn450 455 460 Asp Val Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp ValLeu 465 470 475 480 Val Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp ArgThr Gly Asp 485 490 495 Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr ThrGlu Val Glu Gly 500 505 510 Thr Leu Ser Arg Leu Leu His Met Ala Asp ValAla Val Tyr Gly Val 515 520 525 Glu Val Pro Gly Thr Glu Gly Arg Ala GlyMet Ala Ala Val Ala Ser 530 535 540 Pro Ile Ser Asn Cys Asp Leu Glu SerPhe Ala Gln Thr Leu Lys Lys 545 550 555 560 Glu Leu Pro Leu Tyr Ala ArgPro Ile Phe Leu Arg Phe Leu Pro Glu 565 570 575 Leu His Lys Thr Gly ThrPhe Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585 590 Glu Gly Phe Asp ProSer Val Val Lys Asp Pro Leu Phe Tyr Leu Asp 595 600 605 Ala Arg Lys GlyCys Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg 610 615 620 Ile Gln AlaGly Glu Glu Lys Leu 625 630 36 2885 DNA Homo sapiens 36 aacggcaagtaagcgcaacg caattaatgt gagtagctca ctcattaggc accccaggct 60 ttacactttatgcttccggg ctcgtatgtt gtgtggaatt gtgagcggat accaatttca 120 cacaggaaccagctatgaca tgattacgaa tttaatacga ctcactatag ggaatttggc 180 cctcgaggccaagaattcgg cacgaggggt gctgagcccc tgcgcggttt ctggtgcgta 240 gagactgtaaatcgctgcgc ttctcagtca tcatcatccc agcttttccc ggctcgaatt 300 cagcctccaactcaagctcg cgggaaagac tacctgagag gagaaaagct tctgtccctg 360 gaccttcttctgagggtgga gtcggaggct ccctgctttc cagccgccca gtgacccaag 420 cttaatcttcagcaccactt ggggcgacct tttcggtgca aacctacgat tctgtttctc 480 aggattcctccccatcccgc ttcgccccgg aaaagctgac aagaacttca ggtgtaagcc 540 ctgagtagtgaggatctgcg gtctccgtgg agagctgtgc ctggaagaga aggacgctgg 600 tgggggctgagatcagagct gtcttctggc ccagttgccc ccatgcttct gtcatggcta 660 acagttctaggggctggaat ggtcgtcctg cacttcttgc agaaactcct gttcccttac 720 ttttgggatgacttctggtt cgtgttgaag gtggtgctca ttataattcg gctgaagaag 780 tatgaaaagagaggggagct ggtgactgtg ctggataaat tcttgagtca tgccaaaaga 840 caacctcggaaacctttcat catctatgag ggagacatct acacctatca ggatgtagac 900 aaaaggagcagcagagtggc ccatgtcttc ctgaaccatt cctctctgaa aaagggggac 960 acggtggctctgctgatgag caatgagccg gacttcgttc acgtgtggtt cggcctcgcc 1020 aagctgggctgcgtggtggc ctttctcaac accaacattc gctccaactc cctcctgaat 1080 tgcatccgcgcctgtgggcc cagagcccta gtggtgggcg cagatttgct tggaacggta 1140 gaagaaatccttccaagcct ctcagaaaat atcagtgttt gggggatgaa agattctgtt 1200 ccacaaggtgtaatttcact caaagaaaaa ctgagcacct cacctgatga gcccgtgcca 1260 cgcagccaccatgttgtctc actcctcaag tctacttgtc tttacatttt tacctctgga 1320 acaacaggtctaccaaaagc agctgtgatt agtcagctgc aggttttaag gggttctgct 1380 gtcctgtgggcttttggttg tactgctcat gacattgttt atataaccct tcctctgtat 1440 catagttcagcagctatcct gggaatttct ggatgtgttg agttgggtgc cacttgtgtg 1500 ttaaagaagaaattttcagc aagccagttt tggagtgact gcaagaagta tgatgtgact 1560 gtgtttcagtatattggaga actttgtcgc tacctttgca aacaatctaa gagagaagga 1620 gaaaaggatcataaggtgcg tttggcaatt ggaaatggca tacggagtga tgtatggaga 1680 gaatttttagacagatttgg aaatataaag gtgtgtgaac tttatgcagc taccgaatca 1740 agcatatctttcatgaacta cactgggaga attggagcaa ttgggagaac aaatttgttt 1800 tacaaacttctttccacttt tgacttaata aagtatgact ttcagaaaga tgaacccatg 1860 agaaatgagcagggttggtg tattcatgtg aaaaaaggag aacctggact tctcatttct 1920 cgagtgaatgcaaaaaatcc cttctttggc tatgctgggc cttataagca cacaaaagac 1980 aaattgctttgtgatgtttt taagaaggga gatgtttacc ttaatactgg agacttaata 2040 gtccaggatcaggacaattt cctttatttt tgggaccgta ctggagacac tttcagatgg 2100 aaaggagaaaatgtcgcaac cactgaggtt gctgatgtta ttggaatgtt ggatttcata 2160 caggaagcaaacgtctatgg tgtggctata tcaggttatg aaggaagagc aggaatggct 2220 tctattattttaaaaccaaa tacatcttta gatttggaaa aagtttatga acaagttgta 2280 acatttctaccagcttatgc ttgtccacga tttttaagaa ttcaggaaaa aatggaagca 2340 acaggaacattcaaactatt gaagcatcag ttggtggaag atggatttaa tccactgaaa 2400 atttctgaaccactttactt catggataac ttgaaaaagt cttatgttct actgaccagg 2460 gaactttatgatcaaataat gttaggggaa ataaaacttt aagattttta tatctagaac 2520 tttcatatgctttcttagga agagtgagag gggggtatat gattctttat gaaatgggga 2580 aagggagctaacattaatta tgcatgtact atatttcctt aatatgagag ataatttttt 2640 aattgcataagaattttaat ttcttttaat tgatataaac attagttgat tattcttttt 2700 atctatttggagattcagtg cataactaag tattttcctt aatactaaag attttaaata 2760 ataaatagtggctagcggtt tggacaatca ctaaaaatgt actttctaat aagtaaaatt 2820 tctaattttgaataaaagat taaattttac tgaaaaaaaa aaaaaaaaaa aaaattggcg 2880 gccgc 288537 619 PRT Homo sapiens 37 Met Leu Leu Ser Trp Leu Thr Val Leu Gly AlaGly Met Val Val Leu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro TyrPhe Trp Asp Asp Phe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile IleArg Leu Lys Lys Tyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu AspLys Phe Leu Ser His Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile IleTyr Glu Gly Asp Ile Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg SerSer Arg Val Ala His Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys GlyAsp Thr Val Ala Leu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val HisVal Trp Phe Gly Leu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe LeuAsn Thr Asn Ile Arg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg AlaCys Gly Pro Arg Ala Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu GlyThr Val Glu Glu Ile Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser ValTrp Gly Met Lys Asp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu LysGlu Lys Leu Ser Thr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 HisHis Val Val Ser Leu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230235 240 Val Leu Arg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His245 250 255 Asp Ile Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala AlaIle 260 265 270 Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys ValLeu Lys 275 280 285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys LysLys Tyr Asp 290 295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys ArgTyr Leu Cys Lys 305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp HisLys Val Arg Leu Ala Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val TrpArg Glu Phe Leu Asp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu LeuTyr Ala Ala Thr Glu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr GlyArg Ile Gly Ala Ile Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu LeuSer Thr Phe Asp Leu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp GluPro Met Arg Asn Glu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys GlyGlu Pro Gly Leu Leu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro PhePhe Gly Tyr Ala Gly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 LeuCys Asp Val Phe Lys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460Leu Ile Val Gln Asp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470475 480 Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val485 490 495 Ala Asp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn ValTyr 500 505 510 Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met AlaSer Ile 515 520 525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys ValTyr Glu Gln 530 535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro ArgPhe Leu Arg Ile 545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr PheLys Leu Leu Lys His Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro LeuLys Ile Ser Glu Pro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys SerTyr Val Leu Leu Thr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu GlyGlu Ile Lys Leu 610 615 38 646 PRT Homo sapiens 38 Met Arg Ala Pro GlyAla Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu Trp Leu LeuGly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly Val Tyr ValGly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala ArgArg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu LeuArg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 Ile Phe GlnAla Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala GlyThr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110 Ser AsnAla Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 AspVal Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val 145 150155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Gly Ala165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala Val Ala GluVal 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe Cys Ser GlyAsp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His Leu Leu AspPro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala Gln Ile ProSer Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr SerGly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser ArgTyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr Arg Met GlnAla Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser AlaGly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr Gly Leu ThrVal Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp AspAsp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly GluIle Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350 Glu ArgArg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 AlaIle Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370 375 380Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Pro His Val405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu LeuLeu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln Ala Gly GluPro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu ArgArg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser Lys Lys IleAla His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala Tyr Leu SerGly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe ArgAsp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val SerThr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln ThrAsp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly LysAla Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser Leu Leu AspPro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Pro TyrAla Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr ThrGly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 PheAsp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys 625 630635 640 Ser Gly Ala Phe Ala Leu 645 39 632 PRT Homo sapiens 39 Leu PheSer Lys Leu Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe 1 5 10 15 SerLeu Leu Phe Leu Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg 20 25 30 ValPhe Ile Lys Thr Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu 35 40 45 LeuLys Val Lys Ala Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr 50 55 60 ValPro Ile Leu Phe Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr 65 70 75 80Ala Leu Ile Phe Glu Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu 85 90 95Asp Glu Tyr Ser Ser Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu 100 105110 Ala Ser Gly Asp Val Ala Ala Ile Phe Met Glu Asn Arg Asn Glu Phe 115120 125 Val Gly Leu Trp Leu Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu130 135 140 Ile Asn Thr Asn Leu Arg Arg Asp Ala Leu Leu His Cys Leu ThrThr 145 150 155 160 Ser Arg Ala Arg Ala Leu Val Phe Gly Ser Glu Met AlaSer Ala Ile 165 170 175 Cys Glu Val His Ala Ser Leu Asp Pro Ser Leu SerLeu Phe Cys Ser 180 185 190 Gly Ser Trp Glu Pro Gly Ala Val Pro Pro SerThr Glu His Leu Asp 195 200 205 Pro Leu Leu Lys Asp Ala Pro Lys His LeuPro Ser Cys Pro Asp Lys 210 215 220 Gly Phe Thr Asp Lys Leu Phe Tyr IleTyr Thr Ser Gly Thr Thr Gly 225 230 235 240 Leu Pro Lys Ala Ala Ile ValVal His Ser Arg Tyr Tyr Arg Met Ala 245 250 255 Ala Leu Val Tyr Tyr GlyPhe Arg Met Arg Pro Asn Asp Ile Val Tyr 260 265 270 Asp Cys Leu Pro LeuTyr His Ser Ala Gly Asn Ile Val Gly Ile Gly 275 280 285 Gln Cys Leu LeuHis Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser 290 295 300 Ala Ser ArgPhe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val 305 310 315 320 GlnTyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg 325 330 335Glu Ala Glu Asn Gln His Gln Val Arg Met Ala Leu Gly Asn Gly Leu 340 345350 Arg Gln Ser Ile Trp Thr Asn Phe Ser Ser Arg Phe His Ile Pro Gln 355360 365 Val Ala Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn370 375 380 Phe Asp Ser Gln Val Gly Ala Cys Gly Phe Asn Ser Arg Ile LeuSer 385 390 395 400 Phe Val Tyr Pro Ile Arg Leu Val Arg Val Asn Glu AspThr Met Glu 405 410 415 Leu Ile Arg Gly Pro Asp Gly Val Cys Ile Pro CysGln Pro Gly Glu 420 425 430 Pro Gly Gln Leu Val Gly Arg Ile Ile Gln LysAsp Pro Leu Arg Arg 435 440 445 Phe Asp Gly Tyr Leu Asn Gln Gly Ala AsnAsn Lys Lys Ile Ala Lys 450 455 460 Asp Val Phe Lys Lys Gly Asp Gln AlaTyr Leu Thr Gly Asp Val Leu 465 470 475 480 Val Met Asp Glu Leu Gly TyrLeu Tyr Phe Arg Asp Arg Thr Gly Asp 485 490 495 Thr Phe Arg Trp Lys GlyGlu Asn Val Ser Thr Thr Glu Val Glu Gly 500 505 510 Thr Leu Ser Arg LeuLeu Asp Met Ala Asp Val Ala Val Tyr Gly Val 515 520 525 Glu Val Pro GlyThr Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser 530 535 540 Pro Thr GlyAsn Cys Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys 545 550 555 560 GluLeu Pro Leu Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu 565 570 575Leu His Lys Thr Gly Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg Lys 580 585590 Glu Gly Phe Asp Pro Ala Ile Val Lys Asp Pro Leu Phe Tyr Leu Asp 595600 605 Ala Gln Lys Gly Arg Tyr Val Pro Leu Asp Gln Glu Ala Tyr Ser Arg610 615 620 Ile Gln Ala Gly Glu Glu Lys Leu 625 630 40 619 PRT Homosapiens 40 Met Leu Leu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val ValLeu 1 5 10 15 His Phe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp AspPhe Trp 20 25 30 Phe Val Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys LysTyr Glu 35 40 45 Lys Arg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu SerHis Ala 50 55 60 Lys Arg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly AspIle Tyr 65 70 75 80 Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val AlaHis Val Phe 85 90 95 Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val AlaLeu Leu Met 100 105 110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe GlyLeu Ala Lys Leu 115 120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn IleArg Ser Asn Ser Leu 130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro ArgAla Leu Val Val Gly Ala 145 150 155 160 Asp Leu Leu Gly Thr Val Glu GluIle Leu Pro Ser Leu Ser Glu Asn 165 170 175 Ile Ser Val Trp Gly Met LysAsp Ser Val Pro Gln Gly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu SerThr Ser Pro Asp Glu Pro Val Pro Arg Ser 195 200 205 His His Val Val SerLeu Leu Lys Ser Thr Cys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr ThrGly Leu Pro Lys Ala Ala Val Ile Ser Gln Leu Gln 225 230 235 240 Val LeuArg Gly Ser Ala Val Leu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 AspIle Val Tyr Ile Thr Leu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270Leu Gly Ile Ser Gly Cys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280285 Lys Lys Phe Ser Ala Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290295 300 Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys305 310 315 320 Gln Ser Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg LeuAla Ile 325 330 335 Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe LeuAsp Arg Phe 340 345 350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala ThrGlu Ser Ser Ile 355 360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly AlaIle Gly Arg Thr Asn 370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe AspLeu Ile Lys Tyr Asp Phe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg AsnGlu Gln Gly Trp Cys Ile His Val 405 410 415 Lys Lys Gly Glu Pro Gly LeuLeu Ile Ser Arg Val Asn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr AlaGly Pro Tyr Lys His Thr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val PheLys Lys Gly Asp Val Tyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val GlnAsp Gln Asp Asn Phe Leu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly AspThr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 AlaAsp Val Ile Gly Met Leu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510Gly Val Ala Ile Ser Gly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520525 Ile Leu Lys Pro Asn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530535 540 Val Val Thr Phe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile545 550 555 560 Gln Glu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu LysHis Gln 565 570 575 Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser GluPro Leu Tyr 580 585 590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu LeuThr Arg Glu Leu 595 600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu610 615 41 643 PRT Homo sapiens 41 Met Leu Leu Gly Ala Ser Leu Val GlyVal Leu Leu Phe Ser Lys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr GlnVal Gly Phe Ser Leu Leu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp ArgPhe Ile Arg Val Phe Ile Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly GlyLeu Val Leu Leu Lys Val Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln GluArg Arg Thr Val Pro Ile Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg HisPro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp ThrPhe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe LeuGln Ala Arg Gly Leu Ala Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe MetGlu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala LysLeu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg ArgAsp Ala Leu Leu His Cys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 LeuVal Phe Gly Ser Glu Met Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190Ser Leu Asp Pro Ser Leu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200205 Gly Ala Val Pro Pro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210215 220 Ala Pro Lys His Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro LysAla Ala 245 250 255 Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala LeuVal Tyr Tyr 260 265 270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr AspCys Leu Pro Leu 275 280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile GlyGln Cys Leu Leu His 290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys PheSer Ala Ser Arg Phe Trp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn CysThr Ile Val Gln Tyr Ile Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu AsnGln Pro Pro Arg Glu Ala Glu Asn Gln 340 345 350 His Gln Val Arg Met AlaLeu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser SerArg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr GluCys Asn Cys Ser Leu Gly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly AlaCys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 ArgLeu Val Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440445 Gly Arg Ile Ile Gln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met AspGlu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr PheArg Trp Lys 500 505 510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly ThrLeu Ser Arg Leu 515 520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly ValGlu Val Pro Gly Thr 530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val AlaSer Pro Thr Gly Asn Cys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln ValLeu Glu Lys Glu Leu Pro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu ArgLeu Leu Pro Glu Leu His Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln LysThr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys AspPro Leu Phe Tyr Leu Asp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro LeuAsp Gln Glu Ala Tyr Ser Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu LysLeu 42 643 PRT Mus musculus VARIANT (1)...(643) Xaa = Any Amino Acid 42Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe Ser Lys Leu 1 5 1015 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Xaa Leu 20 2530 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 4045 Val Arg Arg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 5560 Lys Val Arg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 7075 80 Ala Ser Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 8590 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly AsnVal 115 120 125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly LeuTrp Xaa 130 135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile AsnThr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp ThrSer Lys Ala Arg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser AlaIle Cys Glu Ile His Ala 180 185 190 Ser Leu Gly Pro Thr Leu Ser Leu PheCys Ser Gly Ser Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr GluHis Leu Asp Pro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro SerHis Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile TyrThr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val HisSer Arg Tyr Tyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe ArgMet Arg Pro Asp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr HisSer Ser Arg Lys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 GlyMet Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln Tyr Ile Gly Glu 325330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg340 345 350 His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser IleTrp 355 360 365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala GluPhe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe AspSer Arg Val 385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu SerPhe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr MetGlu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln ProGly Gln Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Lys Asp ProLeu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn LysLys Ile Ala Asn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala TyrLeu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu TyrPhe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu AsnVal Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu HisMet Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 GluGly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555560 Asp Leu Glu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565570 575 Ala Arg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly580 585 590 Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe AspPro 595 600 605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg LysGly Cys 610 615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile GlnAla Gly Glu 625 630 635 640 Glu Lys Leu 43 646 PRT Homo sapiens 43 MetArg Ala Pro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15Leu Trp Leu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30Gly Val Tyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45Lys Thr Ala Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60Arg Leu Glu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 7580 Ile Phe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 9095 Asp Ala Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100105 110 Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly115 120 125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val GlyLeu 130 135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu LeuAsn Val 145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu GlyThr Ser Gly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val AlaAla Val Ala Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile LysPhe Cys Ser Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp ThrHis Leu Leu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro LeuAla Gln Ile Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe TyrIle Tyr Thr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile ValVal His Ser Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His AlaTyr Arg Met Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro LeuTyr His Ser Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu IleTyr Gly Leu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330335 Ile Gly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340345 350 Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro355 360 365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln IleGly 370 375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala AsnMet Asp 385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg IleLeu Pro His Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu AspThr Met Glu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro CysGln Ala Gly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln GlnAsp Pro Leu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala ThrSer Lys Lys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp SerAla Tyr Leu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly TyrMet Tyr Phe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg GlyGlu Asn Val Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg LeuLeu Gly Gln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro GlyVal Glu Gly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560Ser Leu Leu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570575 Ala Pro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580585 590 Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly595 600 605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp LeuLys 610 615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr ArgIle Cys 625 630 635 640 Ser Gly Ala Phe Ala Leu 645 44 2710 DNA Musmusculus 44 atgctgcttg gagcctctct ggtgggggcg ctacttgggt ccaagctagtgctgaagctg 60 ccctggaccc aggtgggatt ctccctgttg ctcctgtact tggggtctggtggctggcgt 120 ttcatccggg tcttcatcaa gacggtcagg agagatatct ttggtggcatggtgctcctg 180 aaggtgaaga ccaaggtgcg acggtacctt caggagcgga agacggtgcccctgctgttt 240 gcttcaatgg tacagcgcca cccggacaag acagccctga ttttcgagggcacagacact 300 cactggacct tccgccagct ggatgagtac tccagtagtg tggccaacttcctgcaggcc 360 cggggcctgg cctcaggcaa tgtagttgcc ctctttatgg aaaaccgcaatgagtttgtg 420 ggtctgtggc taggcatggc caagctgggc gtggaggcgg ctctcatcaacaccaacctt 480 aggcgggatg ccctgcgcca ctgtcttgac acctcaaagg cacgagctctcatctttggc 540 agtgagatgg cctcagctat ctgtgagatc catgctagcc tggagcccacactcagcctc 600 ttctgctctg gatcctggga gcccagcaca gtgcccgtca gcacagagcatctggaccct 660 cttctggaag atgccccgaa gcacctgccc agtcacccag acaagggttttacagataag 720 ctcttctaca tctacacatc gggcaccacg gggctaccca aagctgccattgtggtgcac 780 agcaggtatt atcgtatggc ttccctggtg tactatggat tccgcatgcggcctgatgac 840 attgtctatg actgcctccc cctctaccac tcaagcagga aacatcgtggggattggcag 900 tgcttactcc acggcatgac tgtggtgatc cggaagaagt tctcagcctcccggttctgg 960 gatgattgta tcaagtacaa ctgcacagtg gtacagtaca ttggcgagctctgccgctac 1020 ctcctgaacc agccaccccg tgaggctgag tctcggcaca aggtgcgcatggcactgggc 1080 aacggtctcc ggcagtccat ctggaccgac ttctccagcc gtttccacatcccccaggtg 1140 gctgagttct atggggccac tgaatgcaac tgtagcctgg gcaactttgacagccgggtg 1200 ggggcctgtg gcttcaatag ccgcatcctg tcctttgtgt accctatccgtttggtacgt 1260 gtcaatgagg ataccatgga actgatccgg ggacccgatg gagtctgcattccctgtcaa 1320 ccaggtcagc caggccagct ggtgggtcgc atcatccagc aggaccctctgcgccgtttc 1380 gacgggtacc tcaaccaggg tgccaacaac aagaagattg ctaatgatgtcttcaagaag 1440 ggggaccaag cctacctcac tggtgacgtc ctggtgatgg atgagctgggttacctgtac 1500 ttccgagatc gcactgggga cacgttccgc tggaaagggg agaatgtatctaccactgag 1560 gtggagggca cactcagccg cctgcttcat atggcagatg tggcagtttatggtgttgag 1620 gtgccaggaa ctgaaggccg agcaggaatg gctgccgttg caagtcccatcagcaactgt 1680 gacctggaga gctttgcaca gaccttgaaa aaggagctgc ctctgtatgcccgccccatc 1740 ttcctgcgct tcttgcctga gctgcacaag acagggacct tcaagttccagaagacagag 1800 ttgcggaagg agggctttga cccatctgtt gtgaaagacc cgctgttctatctggatgct 1860 cggaagggct gctacgttgc actggaccag gaggcctata cccgcatccaggcaggcgag 1920 gagaagctgt gatttccccc tacatccctc tgagggccag aagatgctggattcagagcc 1980 ctagcgtcca ccccagaggg tcctgggcaa tgccagacca aagctagcagggcccgcacc 2040 tccgccccta ggtgctgatc tcccctctcc caaactgcca agtgactcactgccgcttcc 2100 ccgaccctcc agaggctttc tgtgaaagtc tcatccaagc tgtgtcttctggtccaggcg 2160 tggcccctgg ccccagggtt tctgataggc tcctttagga tggtatcttgggtccagcgg 2220 gccagggtgt gggagaggag tcactaagat ccctccaatc agaagggagcttacaaagga 2280 accaaggcaa agcctgtaga ctcaggaagc taagtggcca gagactatagtggccagtca 2340 tcccatgtcc acagaggatc ttggtccaga gctgccaaag tgtcacctctccctgcctgc 2400 acctctgggg aaaagaggac agcatgtggc cactgggcac ctgtctcaagaagtcaggat 2460 cacacactca gtccttgttt ctccaggttc ccttgttctt gtctcggggagggagggacg 2520 agtgtcctgt ctgtccttcc tgcctgtctg tgagtctgtg ttgcttctccatctgtccta 2580 gcctgagtgt gggtggaaca ggcatgagga gagtgtggct caggggccaataaactctgc 2640 cttgactcct cttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 2700 aaaaaaaaaa 2710 45 643 PRT Mus musculus 45 Met Leu LeuGly Ala Ser Leu Val Gly Ala Leu Leu Phe Ser Lys Leu 1 5 10 15 Val LeuLys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Leu Leu 20 25 30 Tyr LeuGly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val ArgArg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys ValArg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 AlaSer Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 GlyThr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys AlaArg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys GluIle His Ala 180 185 190 Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser GlySer Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu AspPro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro Ser His Pro AspLys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser GlyThr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg TyrTyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg ProAsp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser ArgLys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 Gly Met Thr ValVal Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp AspCys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile Gly Glu 325 330 335 LeuCys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val TyrPro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu IleArg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln ProGly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg ArgPhe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile AlaAsn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr GlyAsp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg AspArg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser ThrThr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu His Met Ala AspVal Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg AlaGly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp LeuGlu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 AlaArg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu625 630 635 640 Glu Lys Leu 46 3694 DNA Homo sapiens 46 tcgacccacggcgtccggga ccccaaagca gaagcccgca cagtaggcac agcgcaccca 60 agaagggtccaggagtctgc agaaacagaa aggtccccgg cctcagcctc ctagtccctg 120 cctgcctcctgcctgagctt ctgggagact gaaggcacgg cttgcagctt caggatgcgg 180 gctccgggtgcgggcgcggc ctcggtggtc tcgctggcgc tgttgtggct gctggggctg 240 ccgtggacctggagcgcggc agcggcgctc ggcgtgtacg tgggcagcgg cggctggcgc 300 ttcctgcgcatcgtctgcaa gaccgcgagg cgagacctct tcggtctctc tgtgctgatc 360 cgcgtgcgcctggagctgcg gcggcaccag cgtgccggcc acaccatccc gcgcatcttt 420 caggcggtagtgcagcgaca gcccgagcgc ctggcgctgg tggatgccgg gaccggcgag 480 tgctggacctttgcgcagct ggacgcctac tccaatgcgg tagccaacct cttccgccag 540 ctgggcttcgcgccgggcga cgtggtggcc atcttcctgg agggccggcc ggagttcgtg 600 gggctgtggctgggcctggc caaggcgggc atggaggccg cgctgctcaa cgtgaacctg 660 cggcgcgagcccctggcctt ctgcctgggc acctcgggcg ctaaggccct gatctttgga 720 ggagaaatggtggcggcggt ggccgaagtg agcgggcatc tggggaaaag tttgatcaag 780 ttctgctctggagacttggg gcccgagggc atcttgccgg acacccacct cctggacccg 840 ctgctgaaggaggcctctac tgcccccttg gcacagatcc ccagcaaggg catggacgat 900 cgtcttttctacatctacac gtcggggacc accgggctgc ccaaggctgc cattgtcgtg 960 cacagcaggtactaccgcat ggcagccttc ggccaccacg cctaccgcat gcaggcggct 1020 gacgtgctctatgactgcct gcccctgtac cactcggcag gaaacatcat cggcgtgggg 1080 cagtgtctcatctatgggct gacagtcgtc ctccgcaaga aattctcggc cagccgcttc 1140 tgggacgactgcatcaagta caactgcacg gtggttcagt acatcgggga gatctgccgc 1200 tacctgctgaagcagccggt gcgcgaggcg gagaggcgac accgcgtgcg cctggcggtg 1260 gggaacgggctgcgtcctgc catctgggag gagttcacgg agcgcttcgg cgtacgccaa 1320 atcggggagttctacggcgc caccgagtgc aactgcagca ttgccaacat ggacggcaag 1380 gtcggctcctgtggtttcaa cagccgcatc ctgccccacg tgtaccccat ccggctggtg 1440 aaggtcaatgaggacacaat ggagctgctg cgggatgccc agggcctctg catcccctgc 1500 caggccggggagcctggcct ccttgtgggt cagatcaacc aacaggaccc gctgcgccgc 1560 ttcgatggctatgtcagcga gagcgccacc agcaagaaga tcgcccacag cgtcttcagc 1620 aagggcgacagcgcctacct ctcaggtgac gtgctagtga tggatgagct gggctacatg 1680 tacttccgggaccgtagcgg ggacaccttc cgctggcgag gggagaacgt ctccaccacc 1740 gaggtggagggcgtgctgag ccgcctgctg ggccagacag acgtggccgt ctatggggtg 1800 gctgttccaggagtggaggg taaggcaggg atggcggccg tcgcagaccc ccacagcctg 1860 ctggaccccaacgcgatata ccaggagctg cagaaggtgc tggcacccta tgcccggccc 1920 atcttcctgcgcctcctgcc ccaggtggac accacaggca ccttcaagat ccagaagacg 1980 aggctgcagcgagagggctt tgacccacgc cagacctcag accggctctt cttcctggac 2040 ctgaagcagggccactacct gcccttaaat gaggcagtct acactcgcat ctgctcgggc 2100 gccttcgccctctgaagctg ttcctctact ggccacaaac tctgggcctg gtgggagagg 2160 ccagcttgagccagacagcg ctgcccaggg gtggccgcct agtacacacc cacctggccg 2220 agctgtacctggcacggccc atcctggact gagaaactgg aacctcagag gaacccgtgc 2280 ctctctgctgccttggtgcc cctgtgtctg cctcctctcc ctgcttttca gcctctgtct 2340 ccttccatccctgtccctgt ctggccttaa ctcttccctc tctttctttt ctttctttct 2400 ttctttttttttaagataga gtctcactct gctgcccggg ctagagtgca gtggtgggat 2460 ctcggctcactgcaacctct gcctcctggg gttcaagtga tcctcccacc tcagcctcct 2520 gagtagctgggattacaggc acccgccacc acgtccagct aatttttata tttttagtag 2580 agacggggtttcaccatgtt ggtcaggctg gtcttgaact cctgacctca ggtgatccgc 2640 tggcctcggcctcccagagt gctgggatta taggcgtgag cctctggccc ggcctttcct 2700 ttttcctctcctctcctgcc gagagtggaa cacacgtgtc ctgggagctg catcttgtgt 2760 agggtccagctgcttttggg gactgcagga atcatctccc ctgggccctg gactcggact 2820 ggggcctccccacctccctc tcggctgtgc cttacggagc cccaatccag gcctcctgtg 2880 gctgttgggttccagatgct gcagctccat gtgacttcca agcaggccct ccgccctccc 2940 tgctgaatggaggagccggg ggtcccccag gccaactgga aaatctccca ggctaggcca 3000 attgccttttgcacttcccc gttcctgtca catttcccca gccccacctt cccctcctga 3060 tgccctgaaagcttccggaa ttgactgtga ccacttggat gtcaccactg tcagcccctg 3120 ccttgatgtccccatttagc catctccatg gagctcctgc tggagggccc tgaaccctgc 3180 actgcgtggctgcccagcca gctgcctcct gtcctgggag gaggcctcct gggtgtcctc 3240 atctggtgtgtctactggag ggtcccacag gagaggcagc agaggggtca ggggaggtct 3300 cctgccgggggttggcctct caagcctcag gggttctagc ctgttgaata taccccacct 3360 ggtgggtggcccctccgatg tccccactga tggctctgac accgtgttgg tggcgatgtc 3420 ccagacaatcccaccaggac ggcccagaca tccctactgg cttcgctggt ggctcatctc 3480 gaacatccacgccagccttt ctggggccgg ccacccaggc cgcctgtccg tctgtcctcc 3540 ctccagcagcaccccctggc ccctggagtg gtggggccat ggcaagagac accgtggcgt 3600 ctcatgtgaactttcctggg cactgtggtt ttatttccta attgatttaa gaaataaacc 3660 tgaagaccgtctggtgaaaa aaaaaaaaaa aaaa 3694 47 646 PRT Homo sapiens 47 Met Arg AlaPro Gly Ala Gly Ala Ala Ser Val Val Ser Leu Ala Leu 1 5 10 15 Leu TrpLeu Leu Gly Leu Pro Trp Thr Trp Ser Ala Ala Ala Ala Leu 20 25 30 Gly ValTyr Val Gly Ser Gly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys ThrAla Arg Arg Asp Leu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg LeuGlu Leu Arg Arg His Gln Arg Ala Gly His Thr Ile Pro Arg 65 70 75 80 IlePhe Gln Ala Val Val Gln Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 AspAla Gly Thr Gly Glu Cys Trp Thr Phe Ala Gln Leu Asp Ala Tyr 100 105 110Ser Asn Ala Val Ala Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120125 Asp Val Val Ala Ile Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130135 140 Trp Leu Gly Leu Ala Lys Ala Gly Met Glu Ala Ala Leu Leu Asn Val145 150 155 160 Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr SerGly Ala 165 170 175 Lys Ala Leu Ile Phe Gly Gly Glu Met Val Ala Ala ValAla Glu Val 180 185 190 Ser Gly His Leu Gly Lys Ser Leu Ile Lys Phe CysSer Gly Asp Leu 195 200 205 Gly Pro Glu Gly Ile Leu Pro Asp Thr His LeuLeu Asp Pro Leu Leu 210 215 220 Lys Glu Ala Ser Thr Ala Pro Leu Ala GlnIle Pro Ser Lys Gly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile TyrThr Ser Gly Thr Thr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val HisSer Arg Tyr Tyr Arg Met Ala Ala Phe 260 265 270 Gly His His Ala Tyr ArgMet Gln Ala Ala Asp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr HisSer Ala Gly Asn Ile Ile Gly Val Gly Gln Cys 290 295 300 Leu Ile Tyr GlyLeu Thr Val Val Leu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg PheTrp Asp Asp Cys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 IleGly Glu Ile Cys Arg Tyr Leu Leu Lys Gln Pro Val Arg Glu Ala 340 345 350Glu Arg Arg His Arg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360365 Ala Ile Trp Glu Glu Phe Thr Glu Arg Phe Gly Val Arg Gln Ile Gly 370375 380 Glu Phe Tyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp385 390 395 400 Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu ProHis Val 405 410 415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr MetGlu Leu Leu 420 425 430 Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys Gln AlaGly Glu Pro Gly 435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp ProLeu Arg Arg Phe Asp 450 455 460 Gly Tyr Val Ser Glu Ser Ala Thr Ser LysLys Ile Ala His Ser Val 465 470 475 480 Phe Ser Lys Gly Asp Ser Ala TyrLeu Ser Gly Asp Val Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met TyrPhe Arg Asp Arg Ser Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu AsnVal Ser Thr Thr Glu Val Glu Gly Val Leu 515 520 525 Ser Arg Leu Leu GlyGln Thr Asp Val Ala Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val GluGly Lys Ala Gly Met Ala Ala Val Ala Asp Pro His 545 550 555 560 Ser LeuLeu Asp Pro Asn Ala Ile Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 AlaPro Tyr Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590Thr Thr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600605 Phe Asp Pro Arg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610615 620 Gln Gly His Tyr Leu Pro Leu Asn Glu Ala Val Tyr Thr Arg Ile Cys625 630 635 640 Ser Gly Ala Phe Ala Leu 645 48 2362 DNA Homo sapiens 48ggaattccaa aaaaaaaaaa tacgactaca cctgctccgg agcccgcggc ggtacctgca 60gcggaggagc tctgtcttcc ccttcatctc acgcgagccc ggcgtcccgc cgcgtgcgcc 120ccggcgcagc ccgccagtcc gcccggagcc cgcccagtcg ccgcgctgca cgcccggggt 180gaaccctctg ccctcgctgg gacagagggc cccgcagccg tcatgctttc cgccatctac 240acagtcctgg cgggactgct gttcctgccg ctcctggtga acctctgctg cccatacttc 300ttccaggaca taggctactt cttgaaggtg gccgccgtgg gccggagggt gcgcagctac 360gggcagcggc ggccggcgcg caccatcctg cgggcgttcc tggagaaagc gcgccagacg 420ccacacaagc cttttctgct cttccgcgac gagactctca cctacgcgca ggtggaccgg 480cgcagcaatc aagtggcccg ggcgctgcac gaccacctcg gcctgcgcca gggagactgc 540gtggcgctcc ttatgggtaa cgagccggcc tacgtgtggc tgtggctggg gctggtgaag 600ctgggctgtg ccatggcgtg cctcaattac aacatccgcg cgaagtccct gctgcactgc 660ttccagtgct gcggggcgaa ggtgctgctg gtgtcgccag aactacaagc agctgtcgaa 720gagatactgc caagccttaa aaaagatgat gtgtccatct attatgtgag cagaacttct 780aacacagatg ggattgactc tttcctggac aaagtggatg aagtatcaac tgaacctatc 840ccagagtcat ggaggtctga agtcactttt tccactcctg ccttatacat ttatacttct 900ggaaccacag gtcttccaaa agcagccatg atcactcatc agcgcatatg gtatggaact 960ggcctcactt ttgtaagcgg attgaaggca gatgatgtca tctatatcac tctgcccttt 1020taccacagtg ctgcactact gattggcatt cacggatgta ttgtggctgg tgctactctt 1080gccttgcgga ctaaattttc agccagccag ttttgggatg actgcagaaa atacaacgtc 1140actgtcattc agtatatcgg tgaactgctt cggtatttat gcaactcacc acagaaacca 1200aatgaccgtg atcataaagt gagactggca ctgggaaatg gcttacgagg agatgtgtgg 1260agacaatttg tcaagagatt tggggacata tgcatctatg agttctatgc tgccactgaa 1320ggcaatattg gatttatgaa ttatgcgaga aaagttggtg ctgttggaag agtaaactac 1380ctacagaaaa aaatcataac ttatgacctg attaaatatg atgtggagaa agatgaacct 1440gtccgagatg aaaatggata ttgcgtcaga gttcccaaag gtgaagttgg acttctggtt 1500tgcaaaatca cacaacttac accatttaat ggctatgctg gagcaaaggc tcagacagag 1560aagaaaaaac tgagagatgt ctttaagaaa ggagacctct atttcaacag tggagatctc 1620ttaatggttg accatgaaaa tttcatctat ttccacgaca gagttggaga tacattccgg 1680tggaaagggg aaaatgtggc caccactgaa gttgctgata cagttggact ggttgatttt 1740gtccaagaag taaatgttta tggagtgcat gtgccagatc atgagggtcg cattggcatg 1800gcctccatca aaatgaaaga aaaccatgaa tttgatggaa agaaactctt tcagcacatt 1860gctgattacc tacctagtta tgcaaggccc cggtttctaa gaatacagga caccattgag 1920atcactggaa cttttaaaca ccgcaaaatg accctggtgg aggagggctt taaccctgct 1980gtcatcaaag atgccttgta tttcttggat gacacagcaa aaatgtatgt gcctatgact 2040gaggacatct ataatgccat aagtgctaaa accctgaaac tctgaatatt cccaggagga 2100taactcaaca tttccagaaa gaaactgaat ggacagccac ttgatataat ccaactttaa 2160tttgattgaa gattgtgagg aaattttgta ggaaatttgc atacccgtaa agggagactt 2220ttttaaataa cagttgagtc tttgcaagta aaaagattta gagattatta tttttcagtg 2280tgcacctact gtttgtattt gcaaactgag cttgttggag ggaaggcatt attttttaaa 2340atacttagta aattaaatga ac 2362 49 620 PRT Homo sapiens 49 Met Leu Ser AlaIle Tyr Thr Val Leu Ala Gly Leu Leu Phe Leu Pro 1 5 10 15 Leu Leu ValAsn Leu Cys Cys Pro Tyr Phe Phe Gln Asp Ile Gly Tyr 20 25 30 Phe Leu LysVal Ala Ala Val Gly Arg Arg Val Arg Ser Tyr Gly Gln 35 40 45 Arg Arg ProAla Arg Thr Ile Leu Arg Ala Phe Leu Glu Lys Ala Arg 50 55 60 Gln Thr ProHis Lys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr AlaGln Val Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp HisLeu Gly Leu Arg Gln Gly Asp Cys Val Ala Leu Leu Met Gly 100 105 110 AsnGlu Pro Ala Tyr Val Trp Leu Trp Leu Gly Leu Val Lys Leu Gly 115 120 125Cys Ala Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135140 His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Val Ser Pro Glu 145150 155 160 Leu Gln Ala Ala Val Glu Glu Ile Leu Pro Ser Leu Lys Lys AspAsp 165 170 175 Val Ser Ile Tyr Tyr Val Ser Arg Thr Ser Asn Thr Asp GlyIle Asp 180 185 190 Ser Phe Leu Asp Lys Val Asp Glu Val Ser Thr Glu ProIle Pro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Ser Thr Pro AlaLeu Tyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala AlaMet Ile Thr His Gln 225 230 235 240 Arg Ile Trp Tyr Gly Thr Gly Leu ThrPhe Val Ser Gly Leu Lys Ala 245 250 255 Asp Asp Val Ile Tyr Ile Thr LeuPro Phe Tyr His Ser Ala Ala Leu 260 265 270 Leu Ile Gly Ile His Gly CysIle Val Ala Gly Ala Thr Leu Ala Leu 275 280 285 Arg Thr Lys Phe Ser AlaSer Gln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Val Thr Val IleGln Tyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Ser ProGln Lys Pro Asn Asp Arg Asp His Lys Val Arg Leu Ala 325 330 335 Leu GlyAsn Gly Leu Arg Gly Asp Val Trp Arg Gln Phe Val Lys Arg 340 345 350 PheGly Asp Ile Cys Ile Tyr Glu Phe Tyr Ala Ala Thr Glu Gly Asn 355 360 365Ile Gly Phe Met Asn Tyr Ala Arg Lys Val Gly Ala Val Gly Arg Val 370 375380 Asn Tyr Leu Gln Lys Lys Ile Ile Thr Tyr Asp Leu Ile Lys Tyr Asp 385390 395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Glu Asn Gly Tyr Cys ValArg 405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Val Cys Lys Ile ThrGln Leu 420 425 430 Thr Pro Phe Asn Gly Tyr Ala Gly Ala Lys Ala Gln ThrGlu Lys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Leu TyrPhe Asn Ser Gly 450 455 460 Asp Leu Leu Met Val Asp His Glu Asn Phe IleTyr Phe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys GlyGlu Asn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Thr Val Gly Leu ValAsp Phe Val Gln Glu Val Asn Val 500 505 510 Tyr Gly Val His Val Pro AspHis Glu Gly Arg Ile Gly Met Ala Ser 515 520 525 Ile Lys Met Lys Glu AsnHis Glu Phe Asp Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ala Asp TyrLeu Pro Ser Tyr Ala Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln AspThr Ile Glu Ile Thr Gly Thr Phe Lys His Arg Lys Met 565 570 575 Thr LeuVal Glu Glu Gly Phe Asn Pro Ala Val Ile Lys Asp Ala Leu 580 585 590 TyrPhe Leu Asp Asp Thr Ala Lys Met Tyr Val Pro Met Thr Glu Asp 595 600 605Ile Tyr Asn Ala Ile Ser Ala Lys Thr Leu Lys Leu 610 615 620 50 1173 DNAHomo sapiens 50 aagttctcgg ctggtcagtt ctgggaagat tgccagcagc acagggtgacggtgttccag 60 tacattgggg agctgtgccg ataccttgtc aaccagcccc cgagcaaggcagaacgtggc 120 cataaggtcc ggctggcagt gggcagcggg ctgcgcccag atacctgggagcgttttgtg 180 cggcgcttcg ggcccctgca ggtgctggag acatatggac tgacagagggcaacgtggcc 240 accatcaact acacaggaca gcggggcgct gtggggcgtg cttcctggctttacaagcat 300 atcttcccct tctccttgat tcgctatgat gtcaccacag gagagccaattcgggacccc 360 caggggcact gtatggccac atctccaggt gagccagggc tgctggtggccccggtaagc 420 cagcagtccc cattcctggg ctatgctggc gggccagagc tggcccaggggaagttgcta 480 aaggatgtct tccggcctgg ggatgttttc ttcaacactg gggacctgctggtctgcgat 540 gaccaaggtt ttctccgctt ccatgatcgt actggagaca ccttcaggtggaagggggag 600 aatgtggcca caaccgaggt ggcagaggtc ttcgaggccc tagattttcttcaggaggtg 660 aacgtctatg gagtcactgt gccagggcat gaaggcaggg ctggaatggcagccctagtt 720 ctgcgtcccc cccacgcttt ggaccttatg cagctctaca cccacgtgtctgagaacttg 780 ccaccttatg cccggccccg attcctcagg ctccaggagt ctttggccaccacagagacc 840 ttcaaacagc agaaagttcg gatggcaaat gagggcttcg accccagcaccctgtctgac 900 ccactgtacg ttctggacca ggctgtaggt gcctacctgc ccctcacaactgcccggtac 960 agcgccctcc tggcaggaaa ccttcgaatc tgagaacttc cacacctgaggcacctgaga 1020 gaggaactct gtggggtggg ggccgttgca ggtgtactgg gctgtcagggatcttttcta 1080 taccagaact gcggtcacta ttttgtaata aatgtggctg gagctgatccagctgtctct 1140 gacaaaaaaa aaaaaaaaaa aaagggcggc cgc 1173 51 330 PRTHomo sapiens 51 Lys Phe Ser Ala Gly Gln Phe Trp Glu Asp Cys Gln Gln HisArg Val 1 5 10 15 Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr LeuVal Asn Gln 20 25 30 Pro Pro Ser Lys Ala Glu Arg Gly His Lys Val Arg LeuAla Val Gly 35 40 45 Ser Gly Leu Arg Pro Asp Thr Trp Glu Arg Phe Val ArgArg Phe Gly 50 55 60 Pro Leu Gln Val Leu Glu Thr Tyr Gly Leu Thr Glu GlyAsn Val Ala 65 70 75 80 Thr Ile Asn Tyr Thr Gly Gln Arg Gly Ala Val GlyArg Ala Ser Trp 85 90 95 Leu Tyr Lys His Ile Phe Pro Phe Ser Leu Ile ArgTyr Asp Val Thr 100 105 110 Thr Gly Glu Pro Ile Arg Asp Pro Gln Gly HisCys Met Ala Thr Ser 115 120 125 Pro Gly Glu Pro Gly Leu Leu Val Ala ProVal Ser Gln Gln Ser Pro 130 135 140 Phe Leu Gly Tyr Ala Gly Gly Pro GluLeu Ala Gln Gly Lys Leu Leu 145 150 155 160 Lys Asp Val Phe Arg Pro GlyAsp Val Phe Phe Asn Thr Gly Asp Leu 165 170 175 Leu Val Cys Asp Asp GlnGly Phe Leu Arg Phe His Asp Arg Thr Gly 180 185 190 Asp Thr Phe Arg TrpLys Gly Glu Asn Val Ala Thr Thr Glu Val Ala 195 200 205 Glu Val Phe GluAla Leu Asp Phe Leu Gln Glu Val Asn Val Tyr Gly 210 215 220 Val Thr ValPro Gly His Glu Gly Arg Ala Gly Met Ala Ala Leu Val 225 230 235 240 LeuArg Pro Pro His Ala Leu Asp Leu Met Gln Leu Tyr Thr His Val 245 250 255Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe Leu Arg Leu Gln 260 265270 Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln Lys Val Arg Met 275280 285 Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu Ser Asp Pro Leu Tyr Val290 295 300 Leu Asp Gln Ala Val Gly Ala Tyr Leu Pro Leu Thr Thr Ala ArgTyr 305 310 315 320 Ser Ala Leu Leu Ala Gly Asn Leu Arg Ile 325 330 522907 DNA Homo sapiens 52 cgacccacgc gtccgggcgg gcggggccgg gcggcgggcggggctggcgg ggcggccggg 60 ccatgcaggg cgcagagccg gctaaaccct gctgagacccggctccgtgc gtccaggggc 120 ggctaatgcc cctcacgctg tctacgctgc tgcaaccgggccgcatctgg acggggcgcc 180 gcgcggcgga gccgacgccg ggccacaatg ctgcttggagcctctctggt gggggtgctg 240 ctgttctcca agctggtgct gaaactgccc tggacccaggtgggattctc cctgttgttc 300 ctctacttgg gatctggcgg ctggcgcttc atccgggtcttcatcaagac catcaggcgc 360 gatatctttg gcggcctggt cctcctgaag gtgaaggcaaaggtgcgaca gtgcctgcag 420 gagcggcgga cagtgcccat tttgtttgcc tctaccgttcggcgccaccc cgacaagacg 480 gccctgatct tcgagggcac agatacccac tggaccttccgccagctgga tgagtactca 540 agcagtgtag ccaacttcct gcaggcccgg ggcctggcctcgggcgatgt ggctgccatc 600 ttcatggaga accgcaatga gttcgtgggc ctatggctgggcatggccaa gctcggtgtg 660 gaggcagccc tcatcaacac caacctgcgg cgggatgctctgctccactg cctcaccacc 720 tcgcgcgcac gggcccttgt ctttggcagc gaaatggcctcagccatctg tgaggtccat 780 gccagcctgg acccctcgct cagcctcttc tgctctggctcctgggagcc cggtgcggtg 840 cctccaagca cagaacacct ggaccctctg ctgaaagatgctcccaagca ccttcccagt 900 tgccctgaca agggcttcac agataaactg ttctacatctacacatccgg caccacaggg 960 ctgcccaagg ccgccatcgt ggtgcacagc aggtattaccgcatggctgc cctggtgtac 1020 tatggattcc gcatgcggcc caacgacatc gtctatgactgcctccccct ctaccactca 1080 gcaggaaaca tcgtgggaat cggccagtgc ctgctgcatggcatgacggt ggtgattcgg 1140 aagaagttct cagcctcccg gttctgggac gattgtatcaagtacaactg cacgattgtg 1200 cagtacattg gtgaactgtg ccgctacctc ctgaaccagccaccgcggga ggcagaaaac 1260 cagcaccagg ttcgcatggc actaggcaat ggcctccggcagtccatctg gaccaacttt 1320 tccagccgct tccacatacc ccaggtggct gagttctacggggccacaga gtgcaactgt 1380 agcctgggca acttcgacag ccaggtgggg gcctgtggtttcaatagccg catcctgtcc 1440 ttcgtgtacc ccatccggtt ggtacgtgtc aacgaggacaccatggagct gatccggggg 1500 cccgacggcg tctgcattcc ctgccagcca ggtgagccgggccagctggt gggccgcatc 1560 atccagaaag accccctgcg ccgcttcgat ggctacctcaaccagggcgc caacaacaag 1620 aagattgcca aggatgtctt caagaagggg gaccaggcctaccttactgg tgatgtgctg 1680 gtgatggacg agctgggcta cctgtacttc cgagaccgcactggggacac gttccgctgg 1740 aaaggtgaga acgtgtccac caccgaggtg gaaggcacactcagccgcct gctggacatg 1800 gctgacgtgg ccgtgtatgg tgtcgaggtg ccaggaaccgagggccgggc cggaatggct 1860 gctgtggcca gccccactgg caactgtgac ctggagcgctttgctcaggt cttggagaag 1920 gaactgcccc tgtatgcgcg ccccatcttc ctgcgcctcctgcctgagct gcacaaaaca 1980 ggaacctaca agttccagaa gacagagcta cggaaggagggctttgaccc ggctattgtg 2040 aaagacccgc tgttctatct agatgcccag aagggccgctacgtcccgct ggaccaagag 2100 gcctacagcc gcatccaggc aggcgaggag aagctgtgattccccccatc cctctgaggg 2160 ccggcggatg ctggatccgg agccccaggt tccgccccagagcggtcctg gacaaggcca 2220 gaccaaagca agcagggcct ggcacctcca tcctgaggtgctgcccctcc atccaaaact 2280 gccaagtgac tcattgcctt cccaaccctt ccagaggctttctgtgaaag tctcatgtcc 2340 aagttccgtc ttctgggctg ggcaggccct ctggttcccaggctgagact gacgggtttt 2400 ctcaggatga tgtcttgggt gagggtaggg agaggacaaggggtcaccga gcccttccca 2460 gagagcaggg agcttataaa tggaaccaga gcagaagtccccagactcag gaagtcaaca 2520 gagtgggcag ggacagtggt agcatccatc tggtggccaaagagaatcgt agccccagag 2580 ctgcccaagt tcactgggct ccacccccac ctccaggaggggaggagagg acctgacatc 2640 tgtaggtggc ccctgatgcc ccatctacag caggaggtcaggaccacgcc cctggcctct 2700 ccccactccc ccatcctcct ccctgggtgg ctgcctgattatccctcagg cagggcctct 2760 cagtccttgt gggtctgtgt cacctccatc tcagtcttggcctggctatg aggggaggag 2820 gaatgggaga gggggctcag gggccaataa actctgccttgagtcctcct aaaaaaaaaa 2880 aaaaaaaaaa aaaaaaaaaa aaaaaaa 2907 53 643 PRTHomo sapiens 53 Met Leu Leu Gly Ala Ser Leu Val Gly Val Leu Leu Phe SerLys Leu 1 5 10 15 Val Leu Lys Leu Pro Trp Thr Gln Val Gly Phe Ser LeuLeu Phe Leu 20 25 30 Tyr Leu Gly Ser Gly Gly Trp Arg Phe Ile Arg Val PheIle Lys Thr 35 40 45 Ile Arg Arg Asp Ile Phe Gly Gly Leu Val Leu Leu LysVal Lys Ala 50 55 60 Lys Val Arg Gln Cys Leu Gln Glu Arg Arg Thr Val ProIle Leu Phe 65 70 75 80 Ala Ser Thr Val Arg Arg His Pro Asp Lys Thr AlaLeu Ile Phe Glu 85 90 95 Gly Thr Asp Thr His Trp Thr Phe Arg Gln Leu AspGlu Tyr Ser Ser 100 105 110 Ser Val Ala Asn Phe Leu Gln Ala Arg Gly LeuAla Ser Gly Asp Val 115 120 125 Ala Ala Ile Phe Met Glu Asn Arg Asn GluPhe Val Gly Leu Trp Leu 130 135 140 Gly Met Ala Lys Leu Gly Val Glu AlaAla Leu Ile Asn Thr Asn Leu 145 150 155 160 Arg Arg Asp Ala Leu Leu HisCys Leu Thr Thr Ser Arg Ala Arg Ala 165 170 175 Leu Val Phe Gly Ser GluMet Ala Ser Ala Ile Cys Glu Val His Ala 180 185 190 Ser Leu Asp Pro SerLeu Ser Leu Phe Cys Ser Gly Ser Trp Glu Pro 195 200 205 Gly Ala Val ProPro Ser Thr Glu His Leu Asp Pro Leu Leu Lys Asp 210 215 220 Ala Pro LysHis Leu Pro Ser Cys Pro Asp Lys Gly Phe Thr Asp Lys 225 230 235 240 LeuPhe Tyr Ile Tyr Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala 245 250 255Ile Val Val His Ser Arg Tyr Tyr Arg Met Ala Ala Leu Val Tyr Tyr 260 265270 Gly Phe Arg Met Arg Pro Asn Asp Ile Val Tyr Asp Cys Leu Pro Leu 275280 285 Tyr His Ser Ala Gly Asn Ile Val Gly Ile Gly Gln Cys Leu Leu His290 295 300 Gly Met Thr Val Val Ile Arg Lys Lys Phe Ser Ala Ser Arg PheTrp 305 310 315 320 Asp Asp Cys Ile Lys Tyr Asn Cys Thr Ile Val Gln TyrIle Gly Glu 325 330 335 Leu Cys Arg Tyr Leu Leu Asn Gln Pro Pro Arg GluAla Glu Asn Gln 340 345 350 His Gln Val Arg Met Ala Leu Gly Asn Gly LeuArg Gln Ser Ile Trp 355 360 365 Thr Asn Phe Ser Ser Arg Phe His Ile ProGln Val Ala Glu Phe Tyr 370 375 380 Gly Ala Thr Glu Cys Asn Cys Ser LeuGly Asn Phe Asp Ser Gln Val 385 390 395 400 Gly Ala Cys Gly Phe Asn SerArg Ile Leu Ser Phe Val Tyr Pro Ile 405 410 415 Arg Leu Val Arg Val AsnGlu Asp Thr Met Glu Leu Ile Arg Gly Pro 420 425 430 Asp Gly Val Cys IlePro Cys Gln Pro Gly Glu Pro Gly Gln Leu Val 435 440 445 Gly Arg Ile IleGln Lys Asp Pro Leu Arg Arg Phe Asp Gly Tyr Leu 450 455 460 Asn Gln GlyAla Asn Asn Lys Lys Ile Ala Lys Asp Val Phe Lys Lys 465 470 475 480 GlyAsp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp Glu Leu 485 490 495Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys 500 505510 Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr Leu Ser Arg Leu 515520 525 Leu Asp Met Ala Asp Val Ala Val Tyr Gly Val Glu Val Pro Gly Thr530 535 540 Glu Gly Arg Ala Gly Met Ala Ala Val Ala Ser Pro Thr Gly AsnCys 545 550 555 560 Asp Leu Glu Arg Phe Ala Gln Val Leu Glu Lys Glu LeuPro Leu Tyr 565 570 575 Ala Arg Pro Ile Phe Leu Arg Leu Leu Pro Glu LeuHis Lys Thr Gly 580 585 590 Thr Tyr Lys Phe Gln Lys Thr Glu Leu Arg LysGlu Gly Phe Asp Pro 595 600 605 Ala Ile Val Lys Asp Pro Leu Phe Tyr LeuAsp Ala Gln Lys Gly Arg 610 615 620 Tyr Val Pro Leu Asp Gln Glu Ala TyrSer Arg Ile Gln Ala Gly Glu 625 630 635 640 Glu Lys Leu 54 1248 DNA Homosapiens misc_feature (1)...(1248) n = A,T,C or G 54 gtcgttgggatcctcggctg cttagatctc ggagccacct gtgttctggc ccccaagttc 60 tctacttcctgcttctggga tgactgtcgg cagcatggcg tgacagtgat cctgtatgtg 120 ggcgagctcctgcgatactt gtgtaacatt ccccagcaac cagaggaccg gacacataca 180 gtccgcctggcaatgggcaa tggactacgg gctgatgtgt ggggagacct tccagcagcg 240 tttcggtcctatttcggatc tngggaagtc ttacgggctt ccacagaagg gcaacatggg 300 gctttagttcaaatattgtt gggggcgctg cggggccctg ggggcaaaga tggagcttgc 360 ctcctccgaatgctgtcccc ctttgagctg gtgcagttcg acatggaggc ggcggagcct 420 gtgagggacaatcagggctt ctgcatccct gtagggctag gggagccggg gctgctgttg 480 accaaggtggtaagccagca acccttcgtg ggctaccgcg gcccccgaga gctgtcggaa 540 cggaagctggtgcgcaacgt gcggcaatcg ggcgacgttt actacaacac cggggacgta 600 ctggccatggaccgcgaagg cttcctctac ttccgcgacc gactcgggga caccttccga 660 tggaagggcgagaacgtgtc cacgcacgag gtggagggcg tgttgtcgca ggtggacttc 720 ttgcaacaggttaacgtgta tggcgtgtgc gtgccaggtt gtgagggtaa ggtgggcatg 780 gctgctgtggcattagcccc cggccagact ttcgacgggg agaagttgta ccagcacgtt 840 cgcgcttggctccctgccta cgctaccccc catttcatcc gcatccagga cgccatggag 900 gtcaccagcacgttcaaact gatgaagacc cggttggtgc gtgagggctt caatgtgggg 960 atcgtggttgaccctctgtt tgtactggac aaccgggccc agtccttccg gcccctgacg 1020 gcagaaatgtaccaggctgt gtgtgaggga acctggaggc tctgatcacc tggccaaccc 1080 actggggtagggatcaaagc cagccacccc caccccaaca cactcggtgt ccctttcatc 1140 ctgggcctgtgtgaatccca gcctggccat accctcaacc tcagtgggct ggaaatgaca 1200 gtgggccctgtagcagtggc agaataaact cagmtgygtt cacagaaa 1248 55 354 PRT Homo sapiensVARIANT (1)...(354) Xaa = Any Amino Acid 55 Val Val Gly Ile Leu Gly CysLeu Asp Leu Gly Ala Thr Cys Val Leu 1 5 10 15 Ala Pro Lys Phe Ser ThrSer Cys Phe Trp Asp Asp Cys Arg Gln His 20 25 30 Gly Val Thr Val Ile LeuTyr Val Gly Glu Leu Leu Arg Tyr Leu Cys 35 40 45 Asn Ile Pro Gln Gln ProGlu Asp Arg Thr His Thr Val Arg Leu Ala 50 55 60 Met Gly Asn Gly Leu ArgAla Asp Val Trp Gly Asp Leu Pro Ala Ala 65 70 75 80 Phe Arg Ser Tyr PheGly Ser Xaa Glu Val Leu Arg Ala Ser Thr Glu 85 90 95 Gly Gln His Gly AlaLeu Val Gln Ile Leu Leu Gly Ala Leu Arg Gly 100 105 110 Pro Gly Gly LysAsp Gly Ala Cys Leu Leu Arg Met Leu Ser Pro Phe 115 120 125 Glu Leu ValGln Phe Asp Met Glu Ala Ala Glu Pro Val Arg Asp Asn 130 135 140 Gln GlyPhe Cys Ile Pro Val Gly Leu Gly Glu Pro Gly Leu Leu Leu 145 150 155 160Thr Lys Val Val Ser Gln Gln Pro Phe Val Gly Tyr Arg Gly Pro Arg 165 170175 Glu Leu Ser Glu Arg Lys Leu Val Arg Asn Val Arg Gln Ser Gly Asp 180185 190 Val Tyr Tyr Asn Thr Gly Asp Val Leu Ala Met Asp Arg Glu Gly Phe195 200 205 Leu Tyr Phe Arg Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys GlyGlu 210 215 220 Asn Val Ser Thr His Glu Val Glu Gly Val Leu Ser Gln ValAsp Phe 225 230 235 240 Leu Gln Gln Val Asn Val Tyr Gly Val Cys Val ProGly Cys Glu Gly 245 250 255 Lys Val Gly Met Ala Ala Val Ala Leu Ala ProGly Gln Thr Phe Asp 260 265 270 Gly Glu Lys Leu Tyr Gln His Val Arg AlaTrp Leu Pro Ala Tyr Ala 275 280 285 Thr Pro His Phe Ile Arg Ile Gln AspAla Met Glu Val Thr Ser Thr 290 295 300 Phe Lys Leu Met Lys Thr Arg LeuVal Arg Glu Gly Phe Asn Val Gly 305 310 315 320 Ile Val Val Asp Pro LeuPhe Val Leu Asp Asn Arg Ala Gln Ser Phe 325 330 335 Arg Pro Leu Thr AlaGlu Met Tyr Gln Ala Val Cys Glu Gly Thr Trp 340 345 350 Arg Leu 56 2885DNA Homo sapiens 56 aacggcaagt aagcgcaacg caattaatgt gagtagctcactcattaggc accccaggct 60 ttacacttta tgcttccggg ctcgtatgtt gtgtggaattgtgagcggat accaatttca 120 cacaggaacc agctatgaca tgattacgaa tttaatacgactcactatag ggaatttggc 180 cctcgaggcc aagaattcgg cacgaggggt gctgagcccctgcgcggttt ctggtgcgta 240 gagactgtaa atcgctgcgc ttctcagtca tcatcatcccagcttttccc ggctcgaatt 300 cagcctccaa ctcaagctcg cgggaaagac tacctgagaggagaaaagct tctgtccctg 360 gaccttcttc tgagggtgga gtcggaggct ccctgctttccagccgccca gtgacccaag 420 cttaatcttc agcaccactt ggggcgacct tttcggtgcaaacctacgat tctgtttctc 480 aggattcctc cccatcccgc ttcgccccgg aaaagctgacaagaacttca ggtgtaagcc 540 ctgagtagtg aggatctgcg gtctccgtgg agagctgtgcctggaagaga aggacgctgg 600 tgggggctga gatcagagct gtcttctggc ccagttgcccccatgcttct gtcatggcta 660 acagttctag gggctggaat ggtcgtcctg cacttcttgcagaaactcct gttcccttac 720 ttttgggatg acttctggtt cgtgttgaag gtggtgctcattataattcg gctgaagaag 780 tatgaaaaga gaggggagct ggtgactgtg ctggataaattcttgagtca tgccaaaaga 840 caacctcgga aacctttcat catctatgag ggagacatctacacctatca ggatgtagac 900 aaaaggagca gcagagtggc ccatgtcttc ctgaaccattcctctctgaa aaagggggac 960 acggtggctc tgctgatgag caatgagccg gacttcgttcacgtgtggtt cggcctcgcc 1020 aagctgggct gcgtggtggc ctttctcaac accaacattcgctccaactc cctcctgaat 1080 tgcatccgcg cctgtgggcc cagagcccta gtggtgggcgcagatttgct tggaacggta 1140 gaagaaatcc ttccaagcct ctcagaaaat atcagtgtttgggggatgaa agattctgtt 1200 ccacaaggtg taatttcact caaagaaaaa ctgagcacctcacctgatga gcccgtgcca 1260 cgcagccacc atgttgtctc actcctcaag tctacttgtctttacatttt tacctctgga 1320 acaacaggtc taccaaaagc agctgtgatt agtcagctgcaggttttaag gggttctgct 1380 gtcctgtggg cttttggttg tactgctcat gacattgtttatataaccct tcctctgtat 1440 catagttcag cagctatcct gggaatttct ggatgtgttgagttgggtgc cacttgtgtg 1500 ttaaagaaga aattttcagc aagccagttt tggagtgactgcaagaagta tgatgtgact 1560 gtgtttcagt atattggaga actttgtcgc tacctttgcaaacaatctaa gagagaagga 1620 gaaaaggatc ataaggtgcg tttggcaatt ggaaatggcatacggagtga tgtatggaga 1680 gaatttttag acagatttgg aaatataaag gtgtgtgaactttatgcagc taccgaatca 1740 agcatatctt tcatgaacta cactgggaga attggagcaattgggagaac aaatttgttt 1800 tacaaacttc tttccacttt tgacttaata aagtatgactttcagaaaga tgaacccatg 1860 agaaatgagc agggttggtg tattcatgtg aaaaaaggagaacctggact tctcatttct 1920 cgagtgaatg caaaaaatcc cttctttggc tatgctgggccttataagca cacaaaagac 1980 aaattgcttt gtgatgtttt taagaaggga gatgtttaccttaatactgg agacttaata 2040 gtccaggatc aggacaattt cctttatttt tgggaccgtactggagacac tttcagatgg 2100 aaaggagaaa atgtcgcaac cactgaggtt gctgatgttattggaatgtt ggatttcata 2160 caggaagcaa acgtctatgg tgtggctata tcaggttatgaaggaagagc aggaatggct 2220 tctattattt taaaaccaaa tacatcttta gatttggaaaaagtttatga acaagttgta 2280 acatttctac cagcttatgc ttgtccacga tttttaagaattcaggaaaa aatggaagca 2340 acaggaacat tcaaactatt gaagcatcag ttggtggaagatggatttaa tccactgaaa 2400 atttctgaac cactttactt catggataac ttgaaaaagtcttatgttct actgaccagg 2460 gaactttatg atcaaataat gttaggggaa ataaaactttaagattttta tatctagaac 2520 tttcatatgc tttcttagga agagtgagag gggggtatatgattctttat gaaatgggga 2580 aagggagcta acattaatta tgcatgtact atatttccttaatatgagag ataatttttt 2640 aattgcataa gaattttaat ttcttttaat tgatataaacattagttgat tattcttttt 2700 atctatttgg agattcagtg cataactaag tattttccttaatactaaag attttaaata 2760 ataaatagtg gctagcggtt tggacaatca ctaaaaatgtactttctaat aagtaaaatt 2820 tctaattttg aataaaagat taaattttac tgaaaaaaaaaaaaaaaaaa aaaattggcg 2880 gccgc 2885 57 619 PRT Homo sapiens 57 Met LeuLeu Ser Trp Leu Thr Val Leu Gly Ala Gly Met Val Val Leu 1 5 10 15 HisPhe Leu Gln Lys Leu Leu Phe Pro Tyr Phe Trp Asp Asp Phe Trp 20 25 30 PheVal Leu Lys Val Val Leu Ile Ile Ile Arg Leu Lys Lys Tyr Glu 35 40 45 LysArg Gly Glu Leu Val Thr Val Leu Asp Lys Phe Leu Ser His Ala 50 55 60 LysArg Gln Pro Arg Lys Pro Phe Ile Ile Tyr Glu Gly Asp Ile Tyr 65 70 75 80Thr Tyr Gln Asp Val Asp Lys Arg Ser Ser Arg Val Ala His Val Phe 85 90 95Leu Asn His Ser Ser Leu Lys Lys Gly Asp Thr Val Ala Leu Leu Met 100 105110 Ser Asn Glu Pro Asp Phe Val His Val Trp Phe Gly Leu Ala Lys Leu 115120 125 Gly Cys Val Val Ala Phe Leu Asn Thr Asn Ile Arg Ser Asn Ser Leu130 135 140 Leu Asn Cys Ile Arg Ala Cys Gly Pro Arg Ala Leu Val Val GlyAla 145 150 155 160 Asp Leu Leu Gly Thr Val Glu Glu Ile Leu Pro Ser LeuSer Glu Asn 165 170 175 Ile Ser Val Trp Gly Met Lys Asp Ser Val Pro GlnGly Val Ile Ser 180 185 190 Leu Lys Glu Lys Leu Ser Thr Ser Pro Asp GluPro Val Pro Arg Ser 195 200 205 His His Val Val Ser Leu Leu Lys Ser ThrCys Leu Tyr Ile Phe Thr 210 215 220 Ser Gly Thr Thr Gly Leu Pro Lys AlaAla Val Ile Ser Gln Leu Gln 225 230 235 240 Val Leu Arg Gly Ser Ala ValLeu Trp Ala Phe Gly Cys Thr Ala His 245 250 255 Asp Ile Val Tyr Ile ThrLeu Pro Leu Tyr His Ser Ser Ala Ala Ile 260 265 270 Leu Gly Ile Ser GlyCys Val Glu Leu Gly Ala Thr Cys Val Leu Lys 275 280 285 Lys Lys Phe SerAla Ser Gln Phe Trp Ser Asp Cys Lys Lys Tyr Asp 290 295 300 Val Thr ValPhe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Cys Lys 305 310 315 320 GlnSer Lys Arg Glu Gly Glu Lys Asp His Lys Val Arg Leu Ala Ile 325 330 335Gly Asn Gly Ile Arg Ser Asp Val Trp Arg Glu Phe Leu Asp Arg Phe 340 345350 Gly Asn Ile Lys Val Cys Glu Leu Tyr Ala Ala Thr Glu Ser Ser Ile 355360 365 Ser Phe Met Asn Tyr Thr Gly Arg Ile Gly Ala Ile Gly Arg Thr Asn370 375 380 Leu Phe Tyr Lys Leu Leu Ser Thr Phe Asp Leu Ile Lys Tyr AspPhe 385 390 395 400 Gln Lys Asp Glu Pro Met Arg Asn Glu Gln Gly Trp CysIle His Val 405 410 415 Lys Lys Gly Glu Pro Gly Leu Leu Ile Ser Arg ValAsn Ala Lys Asn 420 425 430 Pro Phe Phe Gly Tyr Ala Gly Pro Tyr Lys HisThr Lys Asp Lys Leu 435 440 445 Leu Cys Asp Val Phe Lys Lys Gly Asp ValTyr Leu Asn Thr Gly Asp 450 455 460 Leu Ile Val Gln Asp Gln Asp Asn PheLeu Tyr Phe Trp Asp Arg Thr 465 470 475 480 Gly Asp Thr Phe Arg Trp LysGly Glu Asn Val Ala Thr Thr Glu Val 485 490 495 Ala Asp Val Ile Gly MetLeu Asp Phe Ile Gln Glu Ala Asn Val Tyr 500 505 510 Gly Val Ala Ile SerGly Tyr Glu Gly Arg Ala Gly Met Ala Ser Ile 515 520 525 Ile Leu Lys ProAsn Thr Ser Leu Asp Leu Glu Lys Val Tyr Glu Gln 530 535 540 Val Val ThrPhe Leu Pro Ala Tyr Ala Cys Pro Arg Phe Leu Arg Ile 545 550 555 560 GlnGlu Lys Met Glu Ala Thr Gly Thr Phe Lys Leu Leu Lys His Gln 565 570 575Leu Val Glu Asp Gly Phe Asn Pro Leu Lys Ile Ser Glu Pro Leu Tyr 580 585590 Phe Met Asp Asn Leu Lys Lys Ser Tyr Val Leu Leu Thr Arg Glu Leu 595600 605 Tyr Asp Gln Ile Met Leu Gly Glu Ile Lys Leu 610 615 58 3098 DNARattus norvegicus 58 aagttcccac tccagacttc tgcgagaacc cgtgaggaagcagcgagaac cgggggtttg 60 caagccagag aaggatgcgg actccgggag caggaacagcctctgtggcc tcattggggc 120 tgctttggct tctgggactt ccgtggacct ggagcgcggcggcggcgttc ggtgtgtacg 180 tgggtagcgg tggctggcga tttctgcgta tcgtctgcaagacggcgagg cgagacctct 240 ttggcctctc tgttctgatc cgcgtgcggc tagagctacgacgacaccgg cgagcaggag 300 acacgatccc acgcatcttc caggccgtgg cccagcgacagccggagcgc ctggcgctgg 360 tagatgcgag tagcggtatc tgctggacct tcgcacagctagacacctac tccaatgctg 420 tggccaatct gttcctccag ctgggctttg cgccaggcgatgtggtggct gtgttcctgg 480 aaggccggcc cgagttcgtg ggactgtggc tgggcctggccaaggccggt gtagtggctg 540 cgcttctcaa tgtcaacctg aggcgggagc cccttgccttctgcttgggc acatcagctg 600 ccaaggccct catttatggc ggggagatgg cagcggcggtggcggaggtg agtgagcagc 660 tggggaagag cctgctcaag ttctgctctg gagatctggggcctgagagc gtcctgcctg 720 acacgcagct tctggacccc atgcttgctg aggcgcccaccacacccctg gcacaggccc 780 caggcaaggg catggatgat cggctatttt acatctatacttctgggacc accggacttc 840 ctaaggcggc cattgtggtg cacagcaggt actaccgcatcgcagccttc ggccaccatt 900 cctacagcat gcgggccaac gatgtgctct atgactgcctacctctctac cactcagcag 960 ggaacatcat gggcgtggga cagtgtatca tctacgggttaacggtggta ctgcgcaaga 1020 agttctccgc cagccgcttc tgggacgact gtgtcaaatataattgcacg gtagtgcagt 1080 acatcggtga aatatgccgc tacctgctaa ggcagccggttcgcgatgta gagcggcggc 1140 accgcgtgcg cctggccgtg ggtaacggac tgcggccagccatctgggag gagttcacgc 1200 agggtttcgg tgtgcgacag attggcgagt tctacggcgccaccgaatgc aactgcagca 1260 ttgccaacat ggacggcaag gtcggctcct gcggcttcaacagccgtatc ctcacgcatg 1320 tgtaccccat ccgtctggtc aaggtcaacg aggacacgatggagccactg agggactccc 1380 aaggcctctg catcccgtgc cagcccgggg aacctgggcttctcgtgggc cagatcaacc 1440 agcaagaccc tctgcggcgc ttcgatggct atgttagtgacagcgccacc aacaagaaga 1500 ttgcccacag cgtgttccga aagggggaca gcgcctacctttcaggtgac gtgctagtga 1560 tggacgagct ggggtacatg tacttccgtg accgcagcggggataccttc cgatggcgcg 1620 gcgagaacgt atccaccacg gaggtggaag ccgtgctgagccgcctgttg ggccagacgg 1680 acgtggctgt gtatggagtg gctgtgccag gagtggaggggaaaagcggc atggcggcca 1740 ttgcagaccc ccacaaccag ctggacccta actcaatgtaccaggaattg cagaaggttc 1800 ttgcatccta tgcccagccc atcttcctgc gtcttctgccccaagtggat acaacaggca 1860 ccttcaagat ccagaagacc cgactacagc gtgaaggctttgacccccgc cagacctcag 1920 accggctctt ctttctagac ctgaaacagg gacgctacctacccctggat gagagagtcc 1980 atgcccgcat ctgcgcaggc gacttctcac tctgagcctggtgagtggga tggccctgga 2040 cttgtgagac cagggagccg gacacccctg ttcaggtgtttctcctgcct ggccacgtgg 2100 ccagcagcac ctgtgggtgc aggaaactgg aacctgagtggccgggtgtc cctttcctac 2160 aacccaccat gcacacatct agcctctgcc ttggtctttttctccatctc tttcctccgt 2220 gcccagcagg agccccacag acacattggc tgctgtgtcctgcagtggga ccggtgtcta 2280 ggggtccatg ctgcaggctg tgacccgcac tggtgcccacctcccttccc cattgtgcct 2340 taggttcctc cactgtgcgc cggtgaagca agtggggacccacatagctg ttgtccctgc 2400 tgagggttgg tagcaaatgc accctcatgt cagctgggagacacatgcag tctcccactg 2460 acccccaatc aactgaagat actgttttgt attattgttttgagataggg tctcactgtg 2520 gaggccaagc tggcctcagg ctcaccactc tactgcctccgggcaccagc ctgcagtttg 2580 atgacatgta tgcactattg ttctaagggt cttctgagtccctgctttcc cctcatgtcc 2640 taaaaccttc cagaactgac tctgatcact tggatgtagctagtgttggc cctgcccacg 2700 tgtgtcaatt caggggtccc caggcatcat ctctggaggccctaaccttg gcaaagcttg 2760 gatgtcctca catcacagca ggagacccag gaaggttgctgtggtgtctc ttgggcaccc 2820 ctggcggcag ccgtggacat gcttccctgc tgtgatagcccaaactgttg cctatgacat 2880 ttgaggtcta cccttctggc tgccatggtc cccattgagatctttggtga ctcacctcag 2940 ccaccaagcc aggcctctgc cttccttcag ctctaagggcatgaagggtg tggacagagc 3000 agccacaggc tgcccacagt cacccacatg caagtgttatttccttgttt gttttaaaaa 3060 aataaacatg ctgagccttg aaaaaaaaaa aaaaaaaa3098 59 646 PRT Rattus norvegicus 59 Met Arg Thr Pro Gly Ala Gly Thr AlaSer Val Ala Ser Leu Gly Leu 1 5 10 15 Leu Trp Leu Leu Gly Leu Pro TrpThr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Gly Val Tyr Val Gly Ser Gly GlyTrp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp Leu PheGly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg His ArgArg Ala Gly Asp Thr Ile Pro Arg 65 70 75 80 Ile Phe Gln Ala Val Ala GlnArg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly Ile CysTrp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val Ala AsnLeu Phe Leu Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val Ala ValPhe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu Gly LeuAla Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 Asn LeuArg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175 LysAla Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185 190Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195 200205 Gly Pro Glu Ser Val Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu 210215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys Gly Met225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr Thr GlyLeu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg IleAla Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Asn Asp ValLeu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn Ile MetGly Val Gly Gln Cys 290 295 300 Ile Ile Tyr Gly Leu Thr Val Val Leu ArgLys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys Val LysTyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys Arg TyrLeu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Arg Arg His Arg ValArg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp Glu GluPhe Thr Gln Gly Phe Gly Val Arg Gln Ile Gly 370 375 380 Glu Phe Tyr GlyAla Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 Gly LysVal Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415 TyrPro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425 430Arg Asp Ser Gln Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435 440445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp 450455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His Ser Val465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp Val LeuVal Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg Ser GlyAsp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr Glu ValGlu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val Ala ValTyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ser Gly Met AlaAla Ile Ala Asp Pro His 545 550 555 560 Asn Gln Leu Asp Pro Asn Ser MetTyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Gln Pro IlePhe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr Phe LysIle Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro Arg GlnThr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly Arg TyrLeu Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 Ala GlyAsp Phe Ser Leu 645 60 2963 DNA Rattus norvegicus 60 gacacagtactgccgatgtt ggacagagga tcgcttaaca gaacgaaatc tcaaaacaaa 60 ttaacaggacccggttgctt gatttcccaa atcagaaaag gctcgaaatg tctagagggg 120 ctgactgatgcagcggtgac ccggactgga gacagttgga cgcgatcatc tctggtgctt 180 ttgttcaaccttgaaacctt cgccacagga gacttgcctg agcagagaag caaacgtgga 240 gaaacaaagagagatctagc gaaaagcctc tgggaccaag gaggggaggt gggactctgg 300 gttggcggtggcacctgctg ccggctatta ataatagggt cgcgatgcgt ttataaggtg 360 tttgattaaacaaagactct atgagagaag aataactagc aacagcccca cgtctgagtc 420 gtcgcctccgacctttttca acgtgggttc tttgggccga gcgtcgtttg ccgagaacta 480 gatctcacctgaccccagac gctgaaaaca agcgctgtgg catcctgggc cacccaagct 540 gacaagggcgcgccccctga gcacacgagg tgccccacga gggggaggga cccacagccg 600 tcccgcccgcaccgcggtgt ccgctgcggg cacctgcagc cgagccgcca cccgcagtcg 660 cagcgcgtccggcggccgaa cccggtcgtc agctcgtcag cacctgctct gcttctctcc 720 cgcccgccgccgcgctgcac gcctcgagcg ctccctcggc cccggcgggg accggggacc 780 ccgcagccaccgccatgctg cctgtgctct acaccggcct ggcggggctg ctgctgctgc 840 ctctgctgctcacctgctgc tgcccctacc tcctccagga cgtgcggttc ttcctgcaac 900 tggccaacatggcccggcag gtgcgcagct accggcagcg gcgacccgtg cgcaccatcc 960 tgcatgtcttcttggagcaa gcgcgcaaga ccccgcacaa gcccttcctg ctgtttcgcg 1020 acgagacgcttacctacgcc caggtagacc ggcgcagcaa ccaagtagcg cgagcgctgc 1080 atgatcacctgggcctgcgg cagggggatt gcgtggccct cttcatgggc aatgagccgg 1140 cctacgtgtggctctggctg ggactgctca aactgggctg tcccatggcg tgcctcaact 1200 acaacatccgtgccaagtct ctgctacact gctttcagtg ctgcggggcg aaggtgctgc 1260 tggcctccccagagctacac gaagctgtcg aggaggttct tccaaccctg aaaaaggagg 1320 gcgtgtccgtcttctacgta agcagaactt ctaacactaa tggcgtggac acagtactgg 1380 acaaagtagacggggtgtcg gcggacccca tcccggagtc gtggaggtct gaagtcacgt 1440 tcaccacacccgcagtctac atatatactt cgggcaccac aggtcttcca aaggctgcaa 1500 ccattaatcaccatcgcctc tggtatggga ccagccttgc cctgaggtcc ggaattaagg 1560 ctcatgacgtcatctacacc accatgcccc tgtaccacag cgcggcgctc atgattggcc 1620 tccacggatgcattgtggtt ggggctacat ttgctttgcg gagcaaattt tcagccagcc 1680 agttttgggacgactgcagg aaatacaacg ccactgtcat tcagtacatc ggtgaactgc 1740 ttcggtacctctgcaacacg ccccagaaac caaatgaccg ggaccacaaa gtgaaaatag 1800 cactaggaaatggcttacga ggagatgtgt ggagagagtt catcaagaga tttggggaca 1860 ttcacatttatgagttctac gcttccactg aaggcaacat tggatttatg aactatccaa 1920 gaaaaatcggagctgttgga agagaaaatt acctacaaaa aaaagttgta aggcacgagc 1980 tgatcaagtatgacgtggag aaggatgagc ctgtccgtga tgcaaatgga tattgcatca 2040 aagtccccaaaggagaggtt ggactcttga tttgcaaaat cacagagctc acaccatttt 2100 ttggctatgctggaggaaag acccagacag agaagaaaaa gctcagagat gtttttaaga 2160 aaggagacgtctacttcaac agtggcgatc tcctgatgat cgaccgtgaa aatttcatct 2220 attttcacgacagagttgga gacaccttcc ggtggaaagg agagaatgta gctaccacgg 2280 aagtcgctgacattgtggga ctggtagatt ttgttgaaga agtgaatgtt tacggtgtgc 2340 ccgtgccaggtcatgaaggt cgcatcggga tggcctcgat caagatgaaa gaaaactacg 2400 agttcaatggaaagaaactc tttcagcaca tctcggagta cctgcccagt tactcgaggc 2460 ctcggttcctgagaatacaa gataccattg agatcaccgg gacttttaaa caccgcaaag 2520 tgaccctgatggaagagggc tttaacccct cagtcatcaa agataccttg tatttcatgg 2580 atgacacagaaaaaacatac gtgcccatga ctgaggacat ttataatgcc ataattgata 2640 agactctgaagctctgaatg ttgcctggct cctaacactt ccagaaagaa acacaatagg 2700 cctagcatagccccttcaca tgtgtaatcc aactttaact tgattaaagg ttataggtgt 2760 gatttttcctaggaaattat tcatttaaag gacaattgtt tgtttgtttg tttgtttttt 2820 attaattacaccagaacgtt tgcaagtaaa aagatttaaa gtcacttatt tttcaatgtg 2880 cacctgccatttgtccttgc aaacttagct tcttggagag agggccttat ttttttaaag 2940 acataataaactatgtaaac act 2963 61 620 PRT Rattus norvegicus 61 Met Leu Pro Val LeuTyr Thr Gly Leu Ala Gly Leu Leu Leu Leu Pro 1 5 10 15 Leu Leu Leu ThrCys Cys Cys Pro Tyr Leu Leu Gln Asp Val Arg Phe 20 25 30 Phe Leu Gln LeuAla Asn Met Ala Arg Gln Val Arg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro ValArg Thr Ile Leu His Val Phe Leu Glu Gln Ala Arg 50 55 60 Lys Thr Pro HisLys Pro Phe Leu Leu Phe Arg Asp Glu Thr Leu Thr 65 70 75 80 Tyr Ala GlnVal Asp Arg Arg Ser Asn Gln Val Ala Arg Ala Leu His 85 90 95 Asp His LeuGly Leu Arg Gln Gly Asp Cys Val Ala Leu Phe Met Gly 100 105 110 Asn GluPro Ala Tyr Val Trp Leu Trp Leu Gly Leu Leu Lys Leu Gly 115 120 125 CysPro Met Ala Cys Leu Asn Tyr Asn Ile Arg Ala Lys Ser Leu Leu 130 135 140His Cys Phe Gln Cys Cys Gly Ala Lys Val Leu Leu Ala Ser Pro Glu 145 150155 160 Leu His Glu Ala Val Glu Glu Val Leu Pro Thr Leu Lys Lys Glu Gly165 170 175 Val Ser Val Phe Tyr Val Ser Arg Thr Ser Asn Thr Asn Gly ValAsp 180 185 190 Thr Val Leu Asp Lys Val Asp Gly Val Ser Ala Asp Pro IlePro Glu 195 200 205 Ser Trp Arg Ser Glu Val Thr Phe Thr Thr Pro Ala ValTyr Ile Tyr 210 215 220 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala ThrIle Asn His His 225 230 235 240 Arg Leu Trp Tyr Gly Thr Ser Leu Ala LeuArg Ser Gly Ile Lys Ala 245 250 255 His Asp Val Ile Tyr Thr Thr Met ProLeu Tyr His Ser Ala Ala Leu 260 265 270 Met Ile Gly Leu His Gly Cys IleVal Val Gly Ala Thr Phe Ala Leu 275 280 285 Arg Ser Lys Phe Ser Ala SerGln Phe Trp Asp Asp Cys Arg Lys Tyr 290 295 300 Asn Ala Thr Val Ile GlnTyr Ile Gly Glu Leu Leu Arg Tyr Leu Cys 305 310 315 320 Asn Thr Pro GlnLys Pro Asn Asp Arg Asp His Lys Val Lys Ile Ala 325 330 335 Leu Gly AsnGly Leu Arg Gly Asp Val Trp Arg Glu Phe Ile Lys Arg 340 345 350 Phe GlyAsp Ile His Ile Tyr Glu Phe Tyr Ala Ser Thr Glu Gly Asn 355 360 365 IleGly Phe Met Asn Tyr Pro Arg Lys Ile Gly Ala Val Gly Arg Glu 370 375 380Asn Tyr Leu Gln Lys Lys Val Val Arg His Glu Leu Ile Lys Tyr Asp 385 390395 400 Val Glu Lys Asp Glu Pro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys405 410 415 Val Pro Lys Gly Glu Val Gly Leu Leu Ile Cys Lys Ile Thr GluLeu 420 425 430 Thr Pro Phe Phe Gly Tyr Ala Gly Gly Lys Thr Gln Thr GluLys Lys 435 440 445 Lys Leu Arg Asp Val Phe Lys Lys Gly Asp Val Tyr PheAsn Ser Gly 450 455 460 Asp Leu Leu Met Ile Asp Arg Glu Asn Phe Ile TyrPhe His Asp Arg 465 470 475 480 Val Gly Asp Thr Phe Arg Trp Lys Gly GluAsn Val Ala Thr Thr Glu 485 490 495 Val Ala Asp Ile Val Gly Leu Val AspPhe Val Glu Glu Val Asn Val 500 505 510 Tyr Gly Val Pro Val Pro Gly HisGlu Gly Arg Ile Gly Met Ala Ser 515 520 525 Ile Lys Met Lys Glu Asn TyrGlu Phe Asn Gly Lys Lys Leu Phe Gln 530 535 540 His Ile Ser Glu Tyr LeuPro Ser Tyr Ser Arg Pro Arg Phe Leu Arg 545 550 555 560 Ile Gln Asp ThrIle Glu Ile Thr Gly Thr Phe Lys His Arg Lys Val 565 570 575 Thr Leu MetGlu Glu Gly Phe Asn Pro Ser Val Ile Lys Asp Thr Leu 580 585 590 Tyr PheMet Asp Asp Thr Glu Lys Thr Tyr Val Pro Met Thr Glu Asp 595 600 605 IleTyr Asn Ala Ile Ile Asp Lys Thr Leu Lys Leu 610 615 620 62 1350 DNARattus norvegicus 62 gatcagctct tctatatcta cacgtcgggc accacggggctacccaaagc tgccattgtg 60 gtgcacagca ggtattaccg aatggctgcc ctggtgtactatggattccg catgcggcct 120 gatgacattg tctatgactg cctccccctc taccactcagcaggaaacat tgtggggatt 180 ggccagtgcg tactccacgg catgactgtg gtgatccggaagaagttttc agcctcccgg 240 ttctgggatg actgtatcaa gtacaactgc acaattgtacagtacattgg tgagctttgc 300 cgctacctcc tgaaccagcc accccgtgag gctgagtctcggcacaaggt gcgcatggca 360 ctgggcaacg gtctccggca gtccatctgg accgacttctccagccgttt ccacattccc 420 aaggtggccg agttctacgg ggccaccgag tgcaactgtagcttgggcaa ctttgacagc 480 caggtggggg cctgtggctt caatagccgc atcctgtcctttgtgtaccc catccgcttg 540 gtacgagtca atgaggatac catggaactg atccggggacccgatggcgt ctgcattccc 600 tgtcaaccag gccagccagg ccagctggtg ggtcgcatcatccagcagga ccccctacgc 660 cgttttgatg gctacctcaa ccagggtgcc aacaacaagaagattgctag tgatgtcttc 720 aagaaagggg accaagccta cctcactggt gacgtgctggtgatggatga gctgggctac 780 ctgtacttcc gagaccgcac aggggacacg ttccgctggaaaggggagaa tgtgtctacc 840 actgaagtgg agggcacact cagccgcctg cttcagatggcagatgtggc tgtttatggt 900 gttgaggtgc caggagctga gggccgagca ggaatggctgctgtggcaag ccccactagc 960 aactgtgacc tggagagctt tgcacagacc ttgaaaaaggagctgcccct gtacgcccgc 1020 cccatcttcc tccgcttctt gcctgagctg cacaaaacaggaaccttcaa gttccagaag 1080 acagagttgc ggaaggaggg ctttgacccg tctgttgtgaaagacccact cttctatttg 1140 gatgcccgga caggctgcta tgttgcactg gaccaagaggcctatacccg catccaggca 1200 ggcgaggaga agctgtgatt tcccccacat ccctctgagggccagaggat gctggattca 1260 gagccccagc ttccactcca gaaggggtct gggcaaggccagaccaaagc tagcagggcc 1320 cgcaccttca ccctaggtgc tgatccccct 1350 63 405PRT Rattus norvegicus 63 Asp Gln Leu Phe Tyr Ile Tyr Thr Ser Gly Thr ThrGly Leu Pro Lys 1 5 10 15 Ala Ala Ile Val Val His Ser Arg Tyr Tyr ArgMet Ala Ala Leu Val 20 25 30 Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp IleVal Tyr Asp Cys Leu 35 40 45 Pro Leu Tyr His Ser Ala Gly Asn Ile Val GlyIle Gly Gln Cys Val 50 55 60 Leu His Gly Met Thr Val Val Ile Arg Lys LysPhe Ser Ala Ser Arg 65 70 75 80 Phe Trp Asp Asp Cys Ile Lys Tyr Asn CysThr Ile Val Gln Tyr Ile 85 90 95 Gly Glu Leu Cys Arg Tyr Leu Leu Asn GlnPro Pro Arg Glu Ala Glu 100 105 110 Ser Arg His Lys Val Arg Met Ala LeuGly Asn Gly Leu Arg Gln Ser 115 120 125 Ile Trp Thr Asp Phe Ser Ser ArgPhe His Ile Pro Lys Val Ala Glu 130 135 140 Phe Tyr Gly Ala Thr Glu CysAsn Cys Ser Leu Gly Asn Phe Asp Ser 145 150 155 160 Gln Val Gly Ala CysGly Phe Asn Ser Arg Ile Leu Ser Phe Val Tyr 165 170 175 Pro Ile Arg LeuVal Arg Val Asn Glu Asp Thr Met Glu Leu Ile Arg 180 185 190 Gly Pro AspGly Val Cys Ile Pro Cys Gln Pro Gly Gln Pro Gly Gln 195 200 205 Leu ValGly Arg Ile Ile Gln Gln Asp Pro Leu Arg Arg Phe Asp Gly 210 215 220 TyrLeu Asn Gln Gly Ala Asn Asn Lys Lys Ile Ala Ser Asp Val Phe 225 230 235240 Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp Val Leu Val Met Asp 245250 255 Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr Gly Asp Thr Phe Arg260 265 270 Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Gly Thr LeuSer 275 280 285 Arg Leu Leu Gln Met Ala Asp Val Ala Val Tyr Gly Val GluVal Pro 290 295 300 Gly Ala Glu Gly Arg Ala Gly Met Ala Ala Val Ala SerPro Thr Ser 305 310 315 320 Asn Cys Asp Leu Glu Ser Phe Ala Gln Thr LeuLys Lys Glu Leu Pro 325 330 335 Leu Tyr Ala Arg Pro Ile Phe Leu Arg PheLeu Pro Glu Leu His Lys 340 345 350 Thr Gly Thr Phe Lys Phe Gln Lys ThrGlu Leu Arg Lys Glu Gly Phe 355 360 365 Asp Pro Ser Val Val Lys Asp ProLeu Phe Tyr Leu Asp Ala Arg Thr 370 375 380 Gly Cys Tyr Val Ala Leu AspGln Glu Ala Tyr Thr Arg Ile Gln Ala 385 390 395 400 Gly Glu Glu Lys Leu405 64 3217 DNA Mus musculus 64 atgcgggctc ctggagcagg aacagcctctgtggcctcac tggcgctgct ttggtttctg 60 ggacttccgt ggacctggag cgcggcggcggcgttctgtg tgtacgtggg tggcggcggc 120 tggcgctttc tgcgtatcgt ctgcaagacggcgaggcgag acctctttgg cctctctgtt 180 ctgattcgtg ttcggctaga gctgcgacgacaccggcgag caggagacac gatcccgtgc 240 atcttccagg ctgtggcccg gcgacaaccagagcgcctgg cactggtgga cgccagtagt 300 ggtatatgct ggaccttcgc acagctggacacctactcca atgctgtagc caacctgttc 360 cgccagctgg gctttgcacc aggcgatgtggtggctgtgt tcctggaggg ccggccggag 420 ttcgtgggac tgtggctggg cctggccaaggccggtgtgg tggctgctct tctcaatgtc 480 aacctgaggc gggagcccct ggccttctgcctgggcacat cagctgccaa ggccctcatt 540 tatggcgggg agatggcagc ggcggtggcggaggtgagcg agcagctggg gaagagcctc 600 ctcaagttct gctctggaga tctggggcctgagagcatcc tgcctgacac gcagctcctg 660 gaccccatgc ttgctgaggc gcccaccacacccctggcac aagccccagg caagggcatg 720 gatgatcggc tgttttacat ctatacttctgggaccaccg ggcttcctaa ggctgccatt 780 gtggtgcaca gcaggtacta ccgcattgctgcctttggcc accattccta cagcatgcgt 840 gccgccgatg tgctctatga ctgcctgccactctaccact ctgcagggaa catcatgggt 900 gtggggcagt gcgtcatcta cgggttgacggtggtactgc gcaagaagtt ctccgccagc 960 cgcttctggg atgactgtgt caagtacaattgcacggtag tggatgacat aggtgaaatc 1020 tgccgctacc tgctgaggca gccggttcgcgacgtggagc agcgacaccg cgtgcgcctg 1080 gccgtgggta atgggctgcg gccagccatctgggaggagt tcacgcagcg cttcggtgtg 1140 ccacagatcg gcgagttcta cggcgctaccgagtgcaact gcagcattgc caacatggac 1200 ggcaaggtcg gctcctgcgg cttcaacagccgtatcctca cgcatgtgta ccccatccgt 1260 ctggtcaagg tcaatgagga cacgatggagccactgcggg actccgaggg cctctgcatc 1320 ccgtgccagc ccggggaacc cggccttctcgtgggccaga tcaaccagca ggaccctctg 1380 cggcgtttcg atggttatgt tagtgacagtgccaccaaca agaagattgc ccacagcgtt 1440 ttccgaaagg gcgatagcgc ctacctctcaggtgacgtgc tagtgatgga cgagctgggc 1500 tacatgtatt tccgtgaccg cagcggggacaccttccgct ggcgcgggga gaacgtgtcc 1560 accacggagg tggaagccgt gctgagccgcctactgggcc agacggacgt ggctgtgtat 1620 ggggtggctg tgccaggagt ggaggggaaagctggcatgg cagccatcgc agatccccac 1680 agccagttgg accctaactc aatgtaccaggaattacaga aggttcttgc atcctatgct 1740 cggcccatct tcctgcgtct tctgccccaggtggatacca caggcacctt caagatccag 1800 aagacccggc tgcagcgtga aggctttgacccccgtcaga cctcagacag gctcttcttt 1860 ctagacctga agtccggcac gaggtatctacccctggatg agagagtcca tgcccgcatt 1920 tgcgcaggcg acttctcact ctgagcctggagagtgggct gggcctggac tcctgagacc 1980 tgggagcctg acacccctct tcgggtgcttctcctgcctg gccacatgga cagcagcacc 2040 tgtgagagta ggaaaatgga acctgagtggctgggacccc tctcctactt cccactatgc 2100 atccattttg cctctgcctt gatctttttctccatctctt ttctccctac ccagcaggag 2160 ccccacaaac acatgttggc tgctgtgtcctgcagttgga ccagtgtcca ggggtacagg 2220 cttcaggctg tgacccacac tggtacccacctccctttcc tattttgcct taggttcatc 2280 cacggttccc ctgtggagca agtgggggcccacatagctg ctgtccctgc tgagggttgg 2340 tagcaatcac accctcatgt cagctgggagacacgcgcag tctcccactg acccccaatc 2400 aactgaaaat attgttttga ctactttttgtttttttgtt tttttgtttt tttttttttt 2460 cgagacagag tttctctgta tagccctggctgtcctggaa ctcactttgt agaccaggct 2520 ggcctcgaac tcaaaaatcc tcctgactctgcctctgctt cccaagtgct gggattaaag 2580 acgtgcgcca ccaccgcctg gctgttttgtatttttgttt tgttttgacg atagggtctc 2640 actgtggagg ccaagctggc ctcagactccccaccccatt gcctctgggc accattctat 2700 attctcagac tgatgacaat gcactagtgtccctaggagt cttgagtctg cactttcccc 2760 tcatagcctc aagcttccag aactgactctgatcacttgg atgtggctag tgttggctct 2820 acccacatgt gtcaattcag gggtccccaggcatagtctc tggaagccct cacccggaaa 2880 aagcttggag agacccagga aggttgttgtgttctcttgg gcaccccctg gtggcagtcc 2940 tgggcatgct tccgcactgt actggtgcatatagcccaga cctatgacat ttgaggtcta 3000 cccttctggc tcctgtggtc cccattgagatccttggtga ctcacctcag tcaccaagca 3060 gagcctctgc ctgccttcat cttcaaggtcatgaaggatg tggacagagc agctacaggc 3120 tgccagcagt caaccacatg agagtgttacttccttgttg gtttttaaaa aataaatgtg 3180 ctgagcctcg aaaaaaaaaa aaaaaaaaaaaaaaaaa 3217 65 646 PRT Mus musculus 65 Met Arg Ala Pro Gly Ala Gly ThrAla Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly Leu ProTrp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly Gly GlyGly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg Asp LeuPhe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg Arg HisArg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala Val AlaArg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser Gly IleCys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala Val AlaAsn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val Val AlaVal Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp Leu GlyLeu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160 AsnLeu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170 175Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180 185190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu 195200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro Met Leu210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly Lys GlyMet 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly Thr ThrGly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr ArgIle Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala Ala AspVal Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly Asn IleMet Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr Val Val LeuArg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp Cys ValLys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile Cys ArgTyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln Arg His ArgVal Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile Trp GluGlu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 Glu Phe TyrGly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400 GlyLys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410 415Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420 425430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly 435440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg Phe Asp450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala His SerVal 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly Asp ValLeu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp Arg SerGly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr Thr GluVal Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp Val AlaVal Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala Gly MetAla Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp Pro Asn SerMet Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala Arg ProIle Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly Thr PheLys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp Pro ArgGln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln Gly ArgTyr Val Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640 AlaGly Asp Phe Ser Leu 645 66 2338 DNA Mus musculus 66 gggcggaggccgagcccagt cgccagctcc tgctctgctc ctctcccgcc tgccgccgcg 60 ctgcacgcctcgagcactcc ctcggccccg gcggggaccg gggaccccgc agctaccgcc 120 atgctgccagtgctctacac cggcctggcg gggctgctgc tgctgcctct gctgctcacc 180 tgctgctgcccctacctcct ccaagatgtg cggtacttcc tgcggctggc caacatggcc 240 cggcgggtgcgcagctaccg gcagcggcga cccgtgcgta ccatcctgcg ggccttcctg 300 gaacaagcgcgcaagacccc acacaagccc ttcctgctgt tccgagacga gacgctcacc 360 tacgcccaggtggaccggcg cagcaaccaa gtggcgcggg cgctgcacga tcaactgggc 420 ctacgacagggggattgcgt agccctcttc atgggcaatg agccggccta cgtgtggatc 480 tggctgggactgctcaaact gggctgtccc atggcgtgcc tcaactacaa cattcgtgcc 540 aagtctctgctgcactgctt tcaatgctgc ggggcgaagg tgctgctggc ctccccagat 600 ctacaagaagctgtggagga ggttcttcca accctgaaaa aggatgccgt gtccgtcttt 660 tacgtaagcagaacttctaa cacaaatggt gtggacacaa tactggacaa agtagacgga 720 gtgtcggcggaacccacccc ggagtcgtgg aggtctgaag tcacttttac cacgccagca 780 gtatacatttatacttcggg aaccacaggt cttccaaaaa gcggaaccat caatcatcat 840 cgcctaaggtatgggacaag ccttgctatg tcgagtggga atcacggcca aggatgtcat 900 ctataccaacaatgcccctg ttccaacagt gcaacgctca agatcggcct tcacggatgc 960 atcctgggttggggctactt taaccttggc ggggcaaatt ctcaagcaag ccaattttgg 1020 gaacgactggcaggaaatac aacgtcaacg gtcattcagt acattggtga actgcttcgg 1080 tacctgtgcaacacaccgca gaaaccaaat gaccgggacc acaaagtgaa aaaagccctg 1140 ggaaatggcttacgaggaga tgtgtggaga gagttcatca agagatttgg ggacatccac 1200 gtgtatgagttctacgcatc cactgaaggc aacattggat ttgtgaacta tccaaggaaa 1260 atcggtgctgtcgggagagc aaactaccta caaagaaaag ttgcaaggta tgagctgatc 1320 aagtatgacgtggagaagga cgagccggtc cgtgacgcaa atggatattg catcaaagtc 1380 cccaaaggtgaggttggact cttggtttgc aaaatcacac agctcacacc atttattggc 1440 tatgctggaggaaagaccca gacagagaag aaaaaactca gagatgtctt taagaaaggc 1500 gacatctacttcaacagcgg agacctcctg atgatcgacc gtgagaactt cgtctacttt 1560 cacgacagggttggagatac tttccggtgg aaaggagaga acgtagctac cacagaagtc 1620 gctgacatcgtgggactggt agattttgtt gaagaagtga atgtgtatgg cgtgcctgtg 1680 ccaggtcatgagggtcgaat tgggatggcc tccctcaaga tcaaagaaaa ctacgagttc 1740 aatggaaagaaactctttca acacatcgcg gagtacctgc ccagttacgc gaggcctcgg 1800 ttcctgaggatacaagatac cattgagatc actgggactt ttaaacaccg caaagtgacc 1860 ctgatggaagagggcttcaa tcccacagtc atcaaagata ccttgtattt catggatgat 1920 gcagagaaaacatttgtgcc catgactgag aacatttata atgccataat tgataaaact 1980 ctgaagctctgaatattccc tggtggttta gctcatgaca tttccagaaa gaaactcgat 2040 agacctcgcagagccacttc atacgtagaa tccaacttta acttgattga agactataag 2100 gtgcgattttatttttagga aattattcat taaaaggata gttttttttt ttttttttaa 2160 ttacacctgaacctttgcaa gtaaaaagat ttagagacaa ttatttttca atgtgcacct 2220 gccatttgtccttgcaaact aagcttcttg gagagagggc cttatttttt taaagacata 2280 ataaactatattaacactaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2338 67 623 PRT Musmusculus 67 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly Leu Leu Leu LeuPro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu Leu Gln Asp ValArg Tyr 20 25 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg Val Arg Ser TyrArg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala Phe Leu Glu GlnAla Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe Arg Asp Glu ThrLeu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn Gln Val Ala ArgAla Leu His 85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp Cys Val Ala LeuPhe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile Trp Leu Gly LeuLeu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn Tyr Asn Ile ArgAla Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys Gly Ala Lys ValLeu Leu Ala Ser Pro Asp 145 150 155 160 Leu Gln Glu Ala Val Glu Glu ValLeu Pro Thr Leu Lys Lys Asp Ala 165 170 175 Val Ser Val Phe Tyr Val SerArg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Ile Leu Asp Lys ValAsp Gly Val Ser Ala Glu Pro Thr Pro Glu 195 200 205 Ser Trp Arg Ser GluVal Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 Thr Ser Gly ThrThr Gly Leu Pro Lys Ser Gly Thr Ile Asn His His 225 230 235 240 Arg LeuArg Tyr Gly Thr Ser Leu Ala Met Ser Ser Gly Asn His Gly 245 250 255 GlnGly Cys His Leu Tyr Gln Gln Cys Pro Cys Ser Asn Ser Ala Thr 260 265 270Leu Lys Ile Gly Leu His Gly Cys Ile Leu Gly Trp Gly Tyr Phe Asn 275 280285 Leu Gly Gly Ala Asn Ser Gln Ala Ser Gln Phe Trp Glu Arg Leu Ala 290295 300 Gly Asn Thr Thr Ser Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu Arg305 310 315 320 Tyr Leu Cys Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp HisLys Val 325 330 335 Lys Lys Ala Leu Gly Asn Gly Leu Arg Gly Asp Val TrpArg Glu Phe 340 345 350 Ile Lys Arg Phe Gly Asp Ile His Val Tyr Glu PheTyr Ala Ser Thr 355 360 365 Glu Gly Asn Ile Gly Phe Val Asn Tyr Pro ArgLys Ile Gly Ala Val 370 375 380 Gly Arg Ala Asn Tyr Leu Gln Arg Lys ValAla Arg Tyr Glu Leu Ile 385 390 395 400 Lys Tyr Asp Val Glu Lys Asp GluPro Val Arg Asp Ala Asn Gly Tyr 405 410 415 Cys Ile Lys Val Pro Lys GlyGlu Val Gly Leu Leu Val Cys Lys Ile 420 425 430 Thr Gln Leu Thr Pro PheIle Gly Tyr Ala Gly Gly Lys Thr Gln Thr 435 440 445 Glu Lys Lys Lys LeuArg Asp Val Phe Lys Lys Gly Asp Ile Tyr Phe 450 455 460 Asn Ser Gly AspLeu Leu Met Ile Asp Arg Glu Asn Phe Val Tyr Phe 465 470 475 480 His AspArg Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala 485 490 495 ThrThr Glu Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu 500 505 510Val Asn Val Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly 515 520525 Met Ala Ser Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys 530535 540 Leu Phe Gln His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro Arg545 550 555 560 Phe Leu Arg Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr PheLys His 565 570 575 Arg Lys Val Thr Leu Met Glu Glu Gly Phe Asn Pro ThrVal Ile Lys 580 585 590 Asp Thr Leu Tyr Phe Met Asp Asp Ala Glu Lys ThrPhe Val Pro Met 595 600 605 Thr Glu Asn Ile Tyr Asn Ala Ile Ile Asp LysThr Leu Lys Leu 610 615 620 68 1998 DNA Mus musculus 68 gaaagctctgagagcgggtg cagtctggcc tggcgtctcg cgtacctggc ccgggagcag 60 ccgacacacaccttcctcat ccacggcgcg cagcgcttta gctacgcgga ggctgagcgc 120 gagagcaaccggattgctcg cgcctttctg cgcgcacggg gctggaccgg gggccgccga 180 ggctcgggcaggggcagcac tgaggaaggc gcacgcgtgg cgcctccggc tggagatgcg 240 gctgctagagggacgaccgc gccccctctg gcacccgggg cgaccgtggc gctgctcctc 300 ccagcgggcccggatttcct ttggatttgg ttcggactgg ccaaagctgg cctgcgcacg 360 gcctttgtgcccaccgcttt acgccgagga cccctgctgc actgcctccg cagctgcggt 420 gcgagtgcgctcgtgctggc cacagagttc ctggagtccc tggagccgga cctgccggcc 480 ttgagagccatggggctcca cctatgggcg acgggccctg aaactaatgt agctggaatc 540 agcaatttgctatcggaagc agcagaccaa gtggatgagc cagtgccggg gtacctctct 600 gccccccagaacataatgga cacctgcctg tacatcttca cctctggcac tactggcctg 660 cccaaggctgctcgaatcag tcatctgaag gttctacagt gccagggatt ctaccatctg 720 tgtggagtccaccaggagga cgtgatctac ctcgcactcc cactgtacca catgtctggc 780 tcccttctgggcattgtggg ctgcttgggc attggggcca ccgtggtgct gaaacccaag 840 ttctcagctagccagttctg ggacgattgc cagaaacaca gggtgacagt gttccagtac 900 attggggagttgtgccgata cctcgtcaac cagcccccga gcaaggcaga gtttgaccat 960 aaggtgcgcttggcagtggg cagtgggttg cgcccagaca cctgggagcg tttcctgcgg 1020 cgatttggacctctgcagat actggagacg tatggcatga cagagggcaa cgtagctacg 1080 ttcaattacacaggacggca gggtgcagtg gggcgagctt cctggcttta caagcacatc 1140 ttccccttctccttgattcg atacgatgtc atgacagggg agcctattcg gaatgcccag 1200 gggcactgcatgaccacatc tccaggtgag ccaggcctac tggtggcccc agtgagccag 1260 cagtcccccttcctgggcta tgctggggct ccggagctgg ccaaggacaa gctgctgaag 1320 gatgtcttctggtctgggga cgttttcttc aatactgggg acctcttggt ctgtgatgag 1380 caaggctttcttcacttcca cgatcgtact ggagacacca tcaggtggaa gggagagaat 1440 gtggccacaactgaagtggc tgaggtcttg gagaccctgg acttccttca ggaggtgaac 1500 atctatggagtcacggtgcc agggcacgaa ggcagggcag gcatggcggc cttggctctg 1560 cggcccccgcaggctctgaa cctggtgcag ctctacagcc atgtttctga gaacttgcca 1620 ccgtatgcccgacctcggtt tctcaggctc caggaatctt tggccactac tgagaccttc 1680 aaacagcagaaggttaggat ggccaatgag ggctttgacc ccagtgtact gtctgaccca 1740 ctctatgttctggaccaaga tataggggcc tacctgcccc tcacacctgc ccggtacagt 1800 gccctcctgtctggagacct tcgaatctga aaccttccac ttgagggagg ggctcggagg 1860 gtacaggccaccatggctgc accagggagg gttttcgggt atcttttgta tatggagtca 1920 ttattttgtaataaacagct ggagcttaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1980 aaaaaaaaaaaaaaaaaa 1998 69 609 PRT Mus musculus 69 Glu Ser Ser Glu Ser Gly Cys SerLeu Ala Trp Arg Leu Ala Tyr Leu 1 5 10 15 Ala Arg Glu Gln Pro Thr HisThr Phe Leu Ile His Gly Ala Gln Arg 20 25 30 Phe Ser Tyr Ala Glu Ala GluArg Glu Ser Asn Arg Ile Ala Arg Ala 35 40 45 Phe Leu Arg Ala Arg Gly TrpThr Gly Gly Arg Arg Gly Ser Gly Arg 50 55 60 Gly Ser Thr Glu Glu Gly AlaArg Val Ala Pro Pro Ala Gly Asp Ala 65 70 75 80 Ala Ala Arg Gly Thr ThrAla Pro Pro Leu Ala Pro Gly Ala Thr Val 85 90 95 Ala Leu Leu Leu Pro AlaGly Pro Asp Phe Leu Trp Ile Trp Phe Gly 100 105 110 Leu Ala Lys Ala GlyLeu Arg Thr Ala Phe Val Pro Thr Ala Leu Arg 115 120 125 Arg Gly Pro LeuLeu His Cys Leu Arg Ser Cys Gly Ala Ser Ala Leu 130 135 140 Val Leu AlaThr Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu Pro Ala 145 150 155 160 LeuArg Ala Met Gly Leu His Leu Trp Ala Thr Gly Pro Glu Thr Asn 165 170 175Val Ala Gly Ile Ser Asn Leu Leu Ser Glu Ala Ala Asp Gln Val Asp 180 185190 Glu Pro Val Pro Gly Tyr Leu Ser Ala Pro Gln Asn Ile Met Asp Thr 195200 205 Cys Leu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Ala Ala210 215 220 Arg Ile Ser His Leu Lys Val Leu Gln Cys Gln Gly Phe Tyr HisLeu 225 230 235 240 Cys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala LeuPro Leu Tyr 245 250 255 His Met Ser Gly Ser Leu Leu Gly Ile Val Gly CysLeu Gly Ile Gly 260 265 270 Ala Thr Val Val Leu Lys Pro Lys Phe Ser AlaSer Gln Phe Trp Asp 275 280 285 Asp Cys Gln Lys His Arg Val Thr Val PheGln Tyr Ile Gly Glu Leu 290 295 300 Cys Arg Tyr Leu Val Asn Gln Pro ProSer Lys Ala Glu Phe Asp His 305 310 315 320 Lys Val Arg Leu Ala Val GlySer Gly Leu Arg Pro Asp Thr Trp Glu 325 330 335 Arg Phe Leu Arg Arg PheGly Pro Leu Gln Ile Leu Glu Thr Tyr Gly 340 345 350 Met Thr Glu Gly AsnVal Ala Thr Phe Asn Tyr Thr Gly Arg Gln Gly 355 360 365 Ala Val Gly ArgAla Ser Trp Leu Tyr Lys His Ile Phe Pro Phe Ser 370 375 380 Leu Ile ArgTyr Asp Val Met Thr Gly Glu Pro Ile Arg Asn Ala Gln 385 390 395 400 GlyHis Cys Met Thr Thr Ser Pro Gly Glu Pro Gly Leu Leu Val Ala 405 410 415Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Ala Pro Glu 420 425430 Leu Ala Lys Asp Lys Leu Leu Lys Asp Val Phe Trp Ser Gly Asp Val 435440 445 Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Glu Gln Gly Phe Leu450 455 460 His Phe His Asp Arg Thr Gly Asp Thr Ile Arg Trp Lys Gly GluAsn 465 470 475 480 Val Ala Thr Thr Glu Val Ala Glu Val Leu Glu Thr LeuAsp Phe Leu 485 490 495 Gln Glu Val Asn Ile Tyr Gly Val Thr Val Pro GlyHis Glu Gly Arg 500 505 510 Ala Gly Met Ala Ala Leu Ala Leu Arg Pro ProGln Ala Leu Asn Leu 515 520 525 Val Gln Leu Tyr Ser His Val Ser Glu AsnLeu Pro Pro Tyr Ala Arg 530 535 540 Pro Arg Phe Leu Arg Leu Gln Glu SerLeu Ala Thr Thr Glu Thr Phe 545 550 555 560 Lys Gln Gln Lys Val Arg MetAla Asn Glu Gly Phe Asp Pro Ser Val 565 570 575 Leu Ser Asp Pro Leu TyrVal Leu Asp Gln Asp Ile Gly Ala Tyr Leu 580 585 590 Pro Leu Thr Pro AlaArg Tyr Ser Ala Leu Leu Ser Gly Asp Leu Arg 595 600 605 Ile 70 2710 DNAMus musculus 70 atgctgcttg gagcctctct ggtgggggcg ctactgttct ccaagctagtgctgaagctg 60 ccctggaccc aggtgggatt ctccctgttg ctcctgtact tggggtctggtggctggcgt 120 ttcatccggg tcttcatcaa gacggtcagg agagatatct ttggtggcatggtgctcctg 180 aaggtgaaga ccaaggtgcg acggtacctt caggagcgga agacggtgcccctgctgttt 240 gcttcaatgg tacagcgcca cccggacaag acagccctga ttttcgagggcacagacact 300 cactggacct tccgccagct ggatgagtac tccagtagtg tggccaacttcctgcaggcc 360 cggggcctgg cctcaggcaa tgtagttgcc ctctttatgg aaaaccgcaatgagtttgtg 420 ggtctgtggc taggcatggc caagctgggc gtggaggcgg ctctcatcaacaccaacctt 480 aggcgggatg ccctgcgcca ctgtcttgac acctcaaagg cacgagctctcatctttggc 540 agtgagatgg cctcagctat ctgtgagatc catgctagcc tggagcccacactcagcctc 600 ttctgctctg gatcctggga gcccagcaca gtgcccgtca gcacagagcatctggaccct 660 cttctggaag atgccccgaa gcacctgccc agtcacccag acaagggttttacagataag 720 ctcttctaca tctacacatc gggcaccacg gggctaccca aagctgccattgtggtgcac 780 agcaggtatt atcgtatggc ttccctggtg tactatggat tccgcatgcggcctgatgac 840 attgtctatg actgcctccc cctctaccac tcaagcagga aacatcgtggggattggcag 900 tgcttactcc acggcatgac tgtggtgatc cggaagaagt tctcagcctcccggttctgg 960 gatgattgta tcaagtacaa ctgcacagtg gtacagtaca ttggcgagctctgccgctac 1020 ctcctgaacc agccaccccg tgaggctgag tctcggcaca aggtgcgcatggcactgggc 1080 aacggtctcc ggcagtccat ctggaccgac ttctccagcc gtttccacatcccccaggtg 1140 gctgagttct atggggccac tgaatgcaac tgtagcctgg gcaactttgacagccgggtg 1200 ggggcctgtg gcttcaatag ccgcatcctg tcctttgtgt accctatccgtttggtacgt 1260 gtcaatgagg ataccatgga actgatccgg ggacccgatg gagtctgcattccctgtcaa 1320 ccaggtcagc caggccagct ggtgggtcgc atcatccagc aggaccctctgcgccgtttc 1380 gacgggtacc tcaaccaggg tgccaacaac aagaagattg ctaatgatgtcttcaagaag 1440 ggggaccaag cctacctcac tggtgacgtc ctggtgatgg atgagctgggttacctgtac 1500 ttccgagatc gcactgggga cacgttccgc tggaaagggg agaatgtatctaccactgag 1560 gtggagggca cactcagccg cctgcttcat atggcagatg tggcagtttatggtgttgag 1620 gtgccaggaa ctgaaggccg agcaggaatg gctgccgttg caagtcccatcagcaactgt 1680 gacctggaga gctttgcaca gaccttgaaa aaggagctgc ctctgtatgcccgccccatc 1740 ttcctgcgct tcttgcctga gctgcacaag acagggacct tcaagttccagaagacagag 1800 ttgcggaagg agggctttga cccatctgtt gtgaaagacc cgctgttctatctggatgct 1860 cggaagggct gctacgttgc actggaccag gaggcctata cccgcatccaggcaggcgag 1920 gagaagctgt gatttccccc tacatccctc tgagggccag aagatgctggattcagagcc 1980 ctagcgtcca ccccagaggg tcctgggcaa tgccagacca aagctagcagggcccgcacc 2040 tccgccccta ggtgctgatc tcccctctcc caaactgcca agtgactcactgccgcttcc 2100 ccgaccctcc agaggctttc tgtgaaagtc tcatccaagc tgtgtcttctggtccaggcg 2160 tggcccctgg ccccagggtt tctgataggc tcctttagga tggtatcttgggtccagcgg 2220 gccagggtgt gggagaggag tcactaagat ccctccaatc agaagggagcttacaaagga 2280 accaaggcaa agcctgtaga ctcaggaagc taagtggcca gagactatagtggccagtca 2340 tcccatgtcc acagaggatc ttggtccaga gctgccaaag tgtcacctctccctgcctgc 2400 acctctgggg aaaagaggac agcatgtggc cactgggcac ctgtctcaagaagtcaggat 2460 cacacactca gtccttgttt ctccaggttc ccttgttctt gtctcggggagggagggacg 2520 agtgtcctgt ctgtccttcc tgcctgtctg tgagtctgtg ttgcttctccatctgtccta 2580 gcctgagtgt gggtggaaca ggcatgagga gagtgtggct caggggccaataaactctgc 2640 cttgactcct cttaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa 2700 aaaaaaaaaa 2710 71 643 PRT Mus musculus 71 Met Leu LeuGly Ala Ser Leu Val Gly Ala Leu Leu Gly Ser Lys Leu 1 5 10 15 Val LeuLys Leu Pro Trp Thr Gln Val Gly Phe Ser Leu Leu Leu Leu 20 25 30 Tyr LeuGly Ser Gly Gly Trp Arg Phe Ile Arg Val Phe Ile Lys Thr 35 40 45 Val ArgArg Asp Ile Phe Gly Gly Met Val Leu Leu Lys Val Lys Thr 50 55 60 Lys ValArg Arg Tyr Leu Gln Glu Arg Lys Thr Val Pro Leu Leu Phe 65 70 75 80 AlaSer Met Val Gln Arg His Pro Asp Lys Thr Ala Leu Ile Phe Glu 85 90 95 GlyThr Asp Thr His Trp Thr Phe Arg Gln Leu Asp Glu Tyr Ser Ser 100 105 110Ser Val Ala Asn Phe Leu Gln Ala Arg Gly Leu Ala Ser Gly Asn Val 115 120125 Val Ala Leu Phe Met Glu Asn Arg Asn Glu Phe Val Gly Leu Trp Leu 130135 140 Gly Met Ala Lys Leu Gly Val Glu Ala Ala Leu Ile Asn Thr Asn Leu145 150 155 160 Arg Arg Asp Ala Leu Arg His Cys Leu Asp Thr Ser Lys AlaArg Ala 165 170 175 Leu Ile Phe Gly Ser Glu Met Ala Ser Ala Ile Cys GluIle His Ala 180 185 190 Ser Leu Glu Pro Thr Leu Ser Leu Phe Cys Ser GlySer Trp Glu Pro 195 200 205 Ser Thr Val Pro Val Ser Thr Glu His Leu AspPro Leu Leu Glu Asp 210 215 220 Ala Pro Lys His Leu Pro Ser His Pro AspLys Gly Phe Thr Asp Lys 225 230 235 240 Leu Phe Tyr Ile Tyr Thr Ser GlyThr Thr Gly Leu Pro Lys Ala Ala 245 250 255 Ile Val Val His Ser Arg TyrTyr Arg Met Ala Ser Leu Val Tyr Tyr 260 265 270 Gly Phe Arg Met Arg ProAsp Asp Ile Val Tyr Asp Cys Leu Pro Leu 275 280 285 Tyr His Ser Ser ArgLys His Arg Gly Asp Trp Gln Cys Leu Leu His 290 295 300 Gly Met Thr ValVal Ile Arg Lys Lys Phe Ser Ala Ser Arg Phe Trp 305 310 315 320 Asp AspCys Ile Lys Tyr Asn Cys Thr Val Val Gln Tyr Ile Gly Glu 325 330 335 LeuCys Arg Tyr Leu Leu Asn Gln Pro Pro Arg Glu Ala Glu Ser Arg 340 345 350His Lys Val Arg Met Ala Leu Gly Asn Gly Leu Arg Gln Ser Ile Trp 355 360365 Thr Asp Phe Ser Ser Arg Phe His Ile Pro Gln Val Ala Glu Phe Tyr 370375 380 Gly Ala Thr Glu Cys Asn Cys Ser Leu Gly Asn Phe Asp Ser Arg Val385 390 395 400 Gly Ala Cys Gly Phe Asn Ser Arg Ile Leu Ser Phe Val TyrPro Ile 405 410 415 Arg Leu Val Arg Val Asn Glu Asp Thr Met Glu Leu IleArg Gly Pro 420 425 430 Asp Gly Val Cys Ile Pro Cys Gln Pro Gly Gln ProGly Gln Leu Val 435 440 445 Gly Arg Ile Ile Gln Gln Asp Pro Leu Arg ArgPhe Asp Gly Tyr Leu 450 455 460 Asn Gln Gly Ala Asn Asn Lys Lys Ile AlaAsn Asp Val Phe Lys Lys 465 470 475 480 Gly Asp Gln Ala Tyr Leu Thr GlyAsp Val Leu Val Met Asp Glu Leu 485 490 495 Gly Tyr Leu Tyr Phe Arg AspArg Thr Gly Asp Thr Phe Arg Trp Lys 500 505 510 Gly Glu Asn Val Ser ThrThr Glu Val Glu Gly Thr Leu Ser Arg Leu 515 520 525 Leu His Met Ala AspVal Ala Val Tyr Gly Val Glu Val Pro Gly Thr 530 535 540 Glu Gly Arg AlaGly Met Ala Ala Val Ala Ser Pro Ile Ser Asn Cys 545 550 555 560 Asp LeuGlu Ser Phe Ala Gln Thr Leu Lys Lys Glu Leu Pro Leu Tyr 565 570 575 AlaArg Pro Ile Phe Leu Arg Phe Leu Pro Glu Leu His Lys Thr Gly 580 585 590Thr Phe Lys Phe Gln Lys Thr Glu Leu Arg Lys Glu Gly Phe Asp Pro 595 600605 Ser Val Val Lys Asp Pro Leu Phe Tyr Leu Asp Ala Arg Lys Gly Cys 610615 620 Tyr Val Ala Leu Asp Gln Glu Ala Tyr Thr Arg Ile Gln Ala Gly Glu625 630 635 640 Glu Lys Leu 72 2277 DNA Mus musculus 72 cactcatcagagctaagaga gactacacgc tctcatctac ttcagaaaga gccaatgcca 60 tgggtatttggaagaaacta accttactgc tgttgctgct tctgctggtt ggcctggggc 120 agcccccatggccagcagct atggctctgg ccctgcgttg gttcctggga gaccccacat 180 gccttgtgctgcttggcttg gcattgctgg gcagaccctg gatcagctcc tggatgcccc 240 actggctgagcctggtagga gcagctctta ccttattcct attgcctcta cagccacccc 300 cagggctacgctggctgcat aaagatgtgg ctttcacctt caagatgctt ttctatggcc 360 taaagttcaggcgacgcctt aacaaacatc ctccagagac ctttgtggat gctttagagc 420 ggcaagcactggcatggcct gaccgggtgg ccttggtgtg tactgggtct gagggctcct 480 caatcacaaatagccagctg gatgccaggt cctgtcaggc agcatgggtc ctgaaagcaa 540 agctgaaggatgccgtaatc cagaacacaa gagatgctgc tgctatctta gttctcccgt 600 ccaagaccatttctgctttg agtgtgtttc tggggttggc caagttgggc tgccctgtgg 660 cctggatcaatccacacagc cgagggatgc ccttgctaca ctctgtacgg agctctgggg 720 ccagtgtgctgattgtggat ccagacctcc aggagaacct ggaagaagtc cttcccaagc 780 tgctagctgagaacattcac tgcttctacc ttggccacag ctcacccacc ccgggagtag 840 aggctctgggagcttccctg gatgctgcac cttctgaccc agtacctgcc agccttcgag 900 ctacgattaagtggaaatct cctgccatat tcatctttac ttcagggacc actggactcc 960 caaagccagccatcttatca catgagcggg tcatacaagt gagcaacgtg ctgtccttct 1020 gtggatgcagagctgatgat gtggtctatg acgtcctacc tctgtaccat acgatagggc 1080 ttgtccttggattccttggc tgcttacaag ttggagccac ctgtgtcctg gcccccaagt 1140 tctctgcctcccgattctgg gctgagtgcc ggcagcatgg cgtaacagtg atcttgtatg 1200 tgggtgaaatcctgcggtac ttgtgtaacg tccctgagca accagaagac aagatacata 1260 cagtgcgcttggccatggga actggacttc gggcaaatgt gtggaaaaac ttccagcaac 1320 gctttggtcccattcggatc tgggaattct acggatccac agagggcaat gtgggcttaa 1380 tgaactatgtgggccactgc ggggctgtgg gaaggaccag ctgcatcctt cgaatgctga 1440 ctccctttgagcttgtacag ttcgacatag agacagcaga gcctctgagg gacaaacagg 1500 gtttttgcattcctgtggag ccaggaaagc caggacttct tttgaccaag gttcgaaaga 1560 accaacccttcctgggctac cgtggttccc aggccgagtc caatcggaaa cttgttgcga 1620 atgtacgacgcgtaggagac ctgtacttca acactgggga cgtgctgacc ttggaccagg 1680 aaggcttcttctactttcaa gaccgccttg gtgacacctt ccggtggaag ggcgaaaacg 1740 tatctactggagaggtggag tgtgttttgt ctagcctaga cttcctagag gaagtcaatg 1800 tctatggtgtgcctgtgcca gggtgtgagg gtaaggttgg catggctgct gtgaaactgg 1860 ctcctgggaagacttttgat gggcagaagc tataccagca tgtccgctcc tggctccctg 1920 cctatgccacacctcatttc atccgtatcc aggattccct ggagatcaca aacacctaca 1980 agctggtaaagtcacggctg gtgcgtgagg gttttgatgt ggggatcatt gctgaccccc 2040 tctacatactggacaacaag gcccagacct tccggagtct gatgccagat gtgtaccagg 2100 ctgtgtgtgaaggaacctgg aatctctgac cacctagcca actggaaggc aatccaaaag 2160 tgtagagattgacactagtc agcttcacaa agttgtccgg gttccagatg cccatggccc 2220 agtagtacttagagaataaa cttgaatgtg tatacaaaaa aaaaaaaaaa aaaaaaa 2277 73 689 PRT Musmusculus 73 Met Gly Ile Trp Lys Lys Leu Thr Leu Leu Leu Leu Leu Leu LeuLeu 1 5 10 15 Val Gly Leu Gly Gln Pro Pro Trp Pro Ala Ala Met Ala LeuAla Leu 20 25 30 Arg Trp Phe Leu Gly Asp Pro Thr Cys Leu Val Leu Leu GlyLeu Ala 35 40 45 Leu Leu Gly Arg Pro Trp Ile Ser Ser Trp Met Pro His TrpLeu Ser 50 55 60 Leu Val Gly Ala Ala Leu Thr Leu Phe Leu Leu Pro Leu GlnPro Pro 65 70 75 80 Pro Gly Leu Arg Trp Leu His Lys Asp Val Ala Phe ThrPhe Lys Met 85 90 95 Leu Phe Tyr Gly Leu Lys Phe Arg Arg Arg Leu Asn LysHis Pro Pro 100 105 110 Glu Thr Phe Val Asp Ala Leu Glu Arg Gln Ala LeuAla Trp Pro Asp 115 120 125 Arg Val Ala Leu Val Cys Thr Gly Ser Glu GlySer Ser Ile Thr Asn 130 135 140 Ser Gln Leu Asp Ala Arg Ser Cys Gln AlaAla Trp Val Leu Lys Ala 145 150 155 160 Lys Leu Lys Asp Ala Val Ile GlnAsn Thr Arg Asp Ala Ala Ala Ile 165 170 175 Leu Val Leu Pro Ser Lys ThrIle Ser Ala Leu Ser Val Phe Leu Gly 180 185 190 Leu Ala Lys Leu Gly CysPro Val Ala Trp Ile Asn Pro His Ser Arg 195 200 205 Gly Met Pro Leu LeuHis Ser Val Arg Ser Ser Gly Ala Ser Val Leu 210 215 220 Ile Val Asp ProAsp Leu Gln Glu Asn Leu Glu Glu Val Leu Pro Lys 225 230 235 240 Leu LeuAla Glu Asn Ile His Cys Phe Tyr Leu Gly His Ser Ser Pro 245 250 255 ThrPro Gly Val Glu Ala Leu Gly Ala Ser Leu Asp Ala Ala Pro Ser 260 265 270Asp Pro Val Pro Ala Ser Leu Arg Ala Thr Ile Lys Trp Lys Ser Pro 275 280285 Ala Ile Phe Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys Pro Ala 290295 300 Ile Leu Ser His Glu Arg Val Ile Gln Val Ser Asn Val Leu Ser Phe305 310 315 320 Cys Gly Cys Arg Ala Asp Asp Val Val Tyr Asp Val Leu ProLeu Tyr 325 330 335 His Thr Ile Gly Leu Val Leu Gly Phe Leu Gly Cys LeuGln Val Gly 340 345 350 Ala Thr Cys Val Leu Ala Pro Lys Phe Ser Ala SerArg Phe Trp Ala 355 360 365 Glu Cys Arg Gln His Gly Val Thr Val Ile LeuTyr Val Gly Glu Ile 370 375 380 Leu Arg Tyr Leu Cys Asn Val Pro Glu GlnPro Glu Asp Lys Ile His 385 390 395 400 Thr Val Arg Leu Ala Met Gly ThrGly Leu Arg Ala Asn Val Trp Lys 405 410 415 Asn Phe Gln Gln Arg Phe GlyPro Ile Arg Ile Trp Glu Phe Tyr Gly 420 425 430 Ser Thr Glu Gly Asn ValGly Leu Met Asn Tyr Val Gly His Cys Gly 435 440 445 Ala Val Gly Arg ThrSer Cys Ile Leu Arg Met Leu Thr Pro Phe Glu 450 455 460 Leu Val Gln PheAsp Ile Glu Thr Ala Glu Pro Leu Arg Asp Lys Gln 465 470 475 480 Gly PheCys Ile Pro Val Glu Pro Gly Lys Pro Gly Leu Leu Leu Thr 485 490 495 LysVal Arg Lys Asn Gln Pro Phe Leu Gly Tyr Arg Gly Ser Gln Ala 500 505 510Glu Ser Asn Arg Lys Leu Val Ala Asn Val Arg Arg Val Gly Asp Leu 515 520525 Tyr Phe Asn Thr Gly Asp Val Leu Thr Leu Asp Gln Glu Gly Phe Phe 530535 540 Tyr Phe Gln Asp Arg Leu Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn545 550 555 560 Val Ser Thr Gly Glu Val Glu Cys Val Leu Ser Ser Leu AspPhe Leu 565 570 575 Glu Glu Val Asn Val Tyr Gly Val Pro Val Pro Gly CysGlu Gly Lys 580 585 590 Val Gly Met Ala Ala Val Lys Leu Ala Pro Gly LysThr Phe Asp Gly 595 600 605 Gln Lys Leu Tyr Gln His Val Arg Ser Trp LeuPro Ala Tyr Ala Thr 610 615 620 Pro His Phe Ile Arg Ile Gln Asp Ser LeuGlu Ile Thr Asn Thr Tyr 625 630 635 640 Lys Leu Val Lys Ser Arg Leu ValArg Glu Gly Phe Asp Val Gly Ile 645 650 655 Ile Ala Asp Pro Leu Tyr IleLeu Asp Asn Lys Ala Gln Thr Phe Arg 660 665 670 Ser Leu Met Pro Asp ValTyr Gln Ala Val Cys Glu Gly Thr Trp Asn 675 680 685 Leu 74 2221 DNADrosophila melanogaster 74 gctctctggg cctatatcaa gctgctgagg tacacgaagcgccatgagcg gctcaactac 60 acggtggcgg acgtcttcga acgaaatgtt caggcccatccggacaaggt ggctgtggtc 120 agtgagacgc aacgctggac cttccgtcag gtgaacgagcatgcgaacaa ggtggccaat 180 gtgctgcagg ctcagggcta caaaaagggc gatgtggtggccctgttgct ggagaaccgc 240 gccgagtacg tggccacctg gctgggtctc tccaagatcggtgtgatcac accgctgatc 300 aacacgaatc tgcgcggtcc ctccctgctg cacagcatcacggtggccca ttgctcggct 360 ctcatttacg gcgaggactt cctggaagct gtcaccgacgtggccaagga tctgccagcg 420 aacctcacac tcttccagtt caacaacgag aacaacaacagcgagacgga aaagaacata 480 ccgcaggcca agaatctgaa cgcgctgctg accacggccagctatgagaa gcctaacaag 540 acgcaggtta accaccacga caagctggtc tacatctacacctccggcac cacaggattg 600 ccaaaggctg cggttatctc tcactcccgt tatctgtttatcgctgctgg catccactac 660 accatgggtt tccaggagga ggacatcttc tacacgcccttgcctttgta ccacaccgct 720 ggtggcatta tgtgcatggg tcagtcggtg ctctttggctccacggtctc cattcgcaag 780 aagttctcgg catccaacta tttcgccgac tgcgccaagtataatgcaac tattggtcag 840 tatatcggtg agatggctcg ctacattcta gctacgaaaccctcggaata cgaccagaaa 900 caccgagtgc gtctggtctt tggaaacgga ctgcgaccgcagatttggcc acagtttgtg 960 cagcgcttca acattgccaa ggttggcgag ttctacggcgccaccgaggg taatgcgaac 1020 atcatgaatc atgacaacac ggtgggcgcc atcggctttgtgtcgcgcat cctgcccaag 1080 atctacccaa tctcgatcat tcgcgccgat ccggacaccggagagcccat tagagatagg 1140 aatggcctat gccaactgtg cgctcccaac gagccaggcgtattcatcgg caagatcgtc 1200 aaaggaaatc cttctcgcga attcctcgga tacgtcgatgaaaaggcctc cgcgaagaag 1260 attgttaagg atgtgttcaa gcatggcgat atggctttcatctccggaga tctgctggtt 1320 gccgacgaga agggttatct gtacttcaag gatcgcaccggtgacacctt ccgctggaag 1380 ggcgagaatg tttccaccag cgaggtggag gcgcaagtcagcaatgtggc cggttacaag 1440 gataccgtcg tttacggcgt aaccattccg cacaccgagggaagggccgg catggccgcc 1500 atctatgatc cggagcgaga attggacctc gacgtcttcgccgctagctt ggccaaggtg 1560 ctgcccgcgt acgctcgtcc ccagatcatt cgattgctcaccaaggtgga cctgactgga 1620 acctttaagc tgcgcaaggt agacctgcag aaggagggctacgatccgaa cgcgatcaag 1680 gacgcgctgt actaccagac ttccaagggt cggtacgagctgctcacgcc ccaggtttac 1740 gaccaggtgc agcgcaacga aatccgcttc taagagctgcaatagagttg tgtctgaacc 1800 ttgccttttg cccaatatgc tgttaattag tttgtaaggctaagtgtagt agaggaaaat 1860 cgggggaaat cggcagcaaa gatcattcag cctaggagagatgcatccga agcacatttc 1920 catgtcaaca atgcactttt gtatatcgta agcatatatatatcgtatat cgtaaacgta 1980 gttgtatctg catttgtgta gatgatagcc tcctatacgcatttcaattg tttttagcgt 2040 gctaaagaac cttgttaaat gcaatttcag ctattgtttagtcagtttta gtggcattta 2100 cacttccatt ctcgttgcgt ttcgtttttg cctgtacatatgagaagctc tgatgttttt 2160 gtatcaaata aagttttttc cttcaccacg gaccacgtgaaaaaaaaaaa aaaaaaaaaa 2220 a 2221 75 590 PRT Drosophila melanogaster 75Ala Leu Trp Ala Tyr Ile Lys Leu Leu Arg Tyr Thr Lys Arg His Glu 1 5 1015 Arg Leu Asn Tyr Thr Val Ala Asp Val Phe Glu Arg Asn Val Gln Ala 20 2530 His Pro Asp Lys Val Ala Val Val Ser Glu Thr Gln Arg Trp Thr Phe 35 4045 Arg Gln Val Asn Glu His Ala Asn Lys Val Ala Asn Val Leu Gln Ala 50 5560 Gln Gly Tyr Lys Lys Gly Asp Val Val Ala Leu Leu Leu Glu Asn Arg 65 7075 80 Ala Glu Tyr Val Ala Thr Trp Leu Gly Leu Ser Lys Ile Gly Val Ile 8590 95 Thr Pro Leu Ile Asn Thr Asn Leu Arg Gly Pro Ser Leu Leu His Ser100 105 110 Ile Thr Val Ala His Cys Ser Ala Leu Ile Tyr Gly Glu Asp PheLeu 115 120 125 Glu Ala Val Thr Asp Val Ala Lys Asp Leu Pro Ala Asn LeuThr Leu 130 135 140 Phe Gln Phe Asn Asn Glu Asn Asn Asn Ser Glu Thr GluLys Asn Ile 145 150 155 160 Pro Gln Ala Lys Asn Leu Asn Ala Leu Leu ThrThr Ala Ser Tyr Glu 165 170 175 Lys Pro Asn Lys Thr Gln Val Asn His HisAsp Lys Leu Val Tyr Ile 180 185 190 Tyr Thr Ser Gly Thr Thr Gly Leu ProLys Ala Ala Val Ile Ser His 195 200 205 Ser Arg Tyr Leu Phe Ile Ala AlaGly Ile His Tyr Thr Met Gly Phe 210 215 220 Gln Glu Glu Asp Ile Phe TyrThr Pro Leu Pro Leu Tyr His Thr Ala 225 230 235 240 Gly Gly Ile Met CysMet Gly Gln Ser Val Leu Phe Gly Ser Thr Val 245 250 255 Ser Ile Arg LysLys Phe Ser Ala Ser Asn Tyr Phe Ala Asp Cys Ala 260 265 270 Lys Tyr AsnAla Thr Ile Gly Gln Tyr Ile Gly Glu Met Ala Arg Tyr 275 280 285 Ile LeuAla Thr Lys Pro Ser Glu Tyr Asp Gln Lys His Arg Val Arg 290 295 300 LeuVal Phe Gly Asn Gly Leu Arg Pro Gln Ile Trp Pro Gln Phe Val 305 310 315320 Gln Arg Phe Asn Ile Ala Lys Val Gly Glu Phe Tyr Gly Ala Thr Glu 325330 335 Gly Asn Ala Asn Ile Met Asn His Asp Asn Thr Val Gly Ala Ile Gly340 345 350 Phe Val Ser Arg Ile Leu Pro Lys Ile Tyr Pro Ile Ser Ile IleArg 355 360 365 Ala Asp Pro Asp Thr Gly Glu Pro Ile Arg Asp Arg Asn GlyLeu Cys 370 375 380 Gln Leu Cys Ala Pro Asn Glu Pro Gly Val Phe Ile GlyLys Ile Val 385 390 395 400 Lys Gly Asn Pro Ser Arg Glu Phe Leu Gly TyrVal Asp Glu Lys Ala 405 410 415 Ser Ala Lys Lys Ile Val Lys Asp Val PheLys His Gly Asp Met Ala 420 425 430 Phe Ile Ser Gly Asp Leu Leu Val AlaAsp Glu Lys Gly Tyr Leu Tyr 435 440 445 Phe Lys Asp Arg Thr Gly Asp ThrPhe Arg Trp Lys Gly Glu Asn Val 450 455 460 Ser Thr Ser Glu Val Glu AlaGln Val Ser Asn Val Ala Gly Tyr Lys 465 470 475 480 Asp Thr Val Val TyrGly Val Thr Ile Pro His Thr Glu Gly Arg Ala 485 490 495 Gly Met Ala AlaIle Tyr Asp Pro Glu Arg Glu Leu Asp Leu Asp Val 500 505 510 Phe Ala AlaSer Leu Ala Lys Val Leu Pro Ala Tyr Ala Arg Pro Gln 515 520 525 Ile IleArg Leu Leu Thr Lys Val Asp Leu Thr Gly Thr Phe Lys Leu 530 535 540 ArgLys Val Asp Leu Gln Lys Glu Gly Tyr Asp Pro Asn Ala Ile Lys 545 550 555560 Asp Ala Leu Tyr Tyr Gln Thr Ser Lys Gly Arg Tyr Glu Leu Leu Thr 565570 575 Pro Gln Val Tyr Asp Gln Val Gln Arg Asn Glu Ile Arg Phe 580 585590 76 173 DNA Danio rerio 76 agtgtagata ccacaggaac gtttaaaatccagaagacca gactgcaaag ggaaggatac 60 gatccacggc tcacaactga ccagatctacttcctaaact ccagagcagg gcgttacgag 120 cttgtcaacg aggagctgta caatgcatttgaacaagggc aggatttccc ttt 173 77 57 PRT Danio rerio 77 Ser Val Asp ThrThr Gly Thr Phe Lys Ile Gln Lys Thr Arg Leu Gln 1 5 10 15 Arg Glu GlyTyr Asp Pro Arg Leu Thr Thr Asp Gln Ile Tyr Phe Leu 20 25 30 Asn Ser ArgAla Gly Arg Tyr Glu Leu Val Asn Glu Glu Leu Tyr Asn 35 40 45 Ala Phe GluGln Gly Gln Asp Phe Pro 50 55 78 1953 DNA Caenorhabditis elegans 78atgaagctgg aggagcttgt gacagttatg cttctcacag tggctgtcat tgctcagaat 60cttccgattg gagtaatatt ggctggagtt cttattttat acatcacagt ggttcatgga 120gatttcattt atagaagtta tcttacgttg aatagggatt taacaggatt ggctctaatt 180attgaagtca aaatcgacct atggtggagg ttgcatcaga ataaaggaat ccatgaactg 240tttttggata ttgtgaaaaa gaatccaaat aagccggcga tgattgacat cgagacgaat 300acaacagaaa catacgcaga gttcaatgca cattgtaata gatatgccaa ttatttccag 360ggtcttggct atcgatccgg agacgttgtc gccttgtaca tggagaactc ggtcgagttt 420gtggccgcgt ggatgggact cgcaaaaatc ggagttgtaa cggcttggat caactcgaat 480ttgaaaagag agcaacttgt tcattgtatc actgcgagca agacaaaggc gattatcaca 540agtgtaacac ttcagaatat tatgcttgat gctatcgatc agaagctgtt tgatgttgag 600ggaattgagg tttactctgt cggagagccc aagaagaatt ctggattcaa gaatctcaag 660aagaagttgg atgctcaaat tactacggaa ccaaagaccc ttgacatagt agattttaaa 720agtattcttt gcttcatcta tacaagtggt actactggaa tgccaaaagc cgctgtcatg 780aagcacttca gatattactc gattgccgtt ggagccgcaa aatcattcgg aatccgccct 840tctgatcgta tgtacgtctc gatgccaatt tatcacactg cagctggaat tcttggagtt 900gggcaagctc tgttgggtgg atcatcgtgt gtcattagaa aaaaattctc ggctagcaac 960ttttggaggg attgtgtaaa gtatgattgt acagtttcac aatacattgg agagatttgt 1020cggtacttgt tggctcagcc agttgtggaa gaggaatcca ggcatagaat gagattgttg 1080gttggaaacg gactccgtgc tgaaatctgg caaccatttg tagatcgatt ccgtgtcaga 1140attggagaac tttatggttc aactgaagga acttcatctc tcgtgaacat tgacggacat 1200gtcggagctt gcggattctt gccaatatcc ccattaacaa agaaaatgca tccggttcga 1260ttaattaagg ttgatgatgt cactggagaa gcaatccgaa cttccgatgg actttgcatt 1320gcatgtaatc caggagagtc tggagcaatg gtgtcgacga tcagaaaaaa taatccatta 1380ttgcaattcg agggatatct gaataagaag gaaacgaata aaaagattat cagagatgtc 1440ttcgcaaagg gagatagttg ctttttgact ggagatcttc ttcattggga tcgtcttggt 1500tatgtatatt tcaaggatcg tactggagat actttccgtt ggaagggaga gaatgtgtcg 1560actactgaag tcgaggcaat tcttcatcca attactggat tgtctgatgc aactgtttat 1620ggtgtagagg ttcctcaaag agagggaaga gttggaatgg cgtcagttgt tcgagttgta 1680tcgcatgagg aagatgaaac tcaatttgtt catagagttg gagcaagact tgcctcttcg 1740cttaccagct acgcgattcc tcagtttatg cgaatttgtc aggatgttga gaaaacaggt 1800acattcaaac ttgtgaagac gaatctacaa cgattaggta tcatggatgc tccttcagat 1860tcaatttaca tctacaattc tgaaaatcgc aattttgtgc cgttcgacaa tgatttgagg 1920tgcaaggtct cactgggaag ttatccattt taa 1953 79 650 PRT Caenorhabditiselegans 79 Met Lys Leu Glu Glu Leu Val Thr Val Met Leu Leu Thr Val AlaVal 1 5 10 15 Ile Ala Gln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly ValLeu Ile 20 25 30 Leu Tyr Ile Thr Val Val His Gly Asp Phe Ile Tyr Arg SerTyr Leu 35 40 45 Thr Leu Asn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile GluVal Lys 50 55 60 Ile Asp Leu Trp Trp Arg Leu His Gln Asn Lys Gly Ile HisGlu Leu 65 70 75 80 Phe Leu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro AlaMet Ile Asp 85 90 95 Ile Glu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe AsnAla His Cys 100 105 110 Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly TyrArg Ser Gly Asp 115 120 125 Val Val Ala Leu Tyr Met Glu Asn Ser Val GluPhe Val Ala Ala Trp 130 135 140 Met Gly Leu Ala Lys Ile Gly Val Val ThrAla Trp Ile Asn Ser Asn 145 150 155 160 Leu Lys Arg Glu Gln Leu Val HisCys Ile Thr Ala Ser Lys Thr Lys 165 170 175 Ala Ile Ile Thr Ser Val ThrLeu Gln Asn Ile Met Leu Asp Ala Ile 180 185 190 Asp Gln Lys Leu Phe AspVal Glu Gly Ile Glu Val Tyr Ser Val Gly 195 200 205 Glu Pro Lys Lys AsnSer Gly Phe Lys Asn Leu Lys Lys Lys Leu Asp 210 215 220 Ala Gln Ile ThrThr Glu Pro Lys Thr Leu Asp Ile Val Asp Phe Lys 225 230 235 240 Ser IleLeu Cys Phe Ile Tyr Thr Ser Gly Thr Thr Gly Met Pro Lys 245 250 255 AlaAla Val Met Lys His Phe Arg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270Ala Lys Ser Phe Gly Ile Arg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280285 Pro Ile Tyr His Thr Ala Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290295 300 Leu Gly Gly Ser Ser Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn305 310 315 320 Phe Trp Arg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser GlnTyr Ile 325 330 335 Gly Glu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val ValGlu Glu Glu 340 345 350 Ser Arg His Arg Met Arg Leu Leu Val Gly Asn GlyLeu Arg Ala Glu 355 360 365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg ValArg Ile Gly Glu Leu 370 375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser LeuVal Asn Ile Asp Gly His 385 390 395 400 Val Gly Ala Cys Gly Phe Leu ProIle Ser Pro Leu Thr Lys Lys Met 405 410 415 His Pro Val Arg Leu Ile LysVal Asp Asp Val Thr Gly Glu Ala Ile 420 425 430 Arg Thr Ser Asp Gly LeuCys Ile Ala Cys Asn Pro Gly Glu Ser Gly 435 440 445 Ala Met Val Ser ThrIle Arg Lys Asn Asn Pro Leu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu AsnLys Lys Glu Thr Asn Lys Lys Ile Ile Arg Asp Val 465 470 475 480 Phe AlaLys Gly Asp Ser Cys Phe Leu Thr Gly Asp Leu Leu His Trp 485 490 495 AspArg Leu Gly Tyr Val Tyr Phe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520525 His Pro Ile Thr Gly Leu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530535 540 Pro Gln Arg Glu Gly Arg Val Gly Met Ala Ser Val Val Arg Val Val545 550 555 560 Ser His Glu Glu Asp Glu Thr Gln Phe Val His Arg Val GlyAla Arg 565 570 575 Leu Ala Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln PheMet Arg Ile 580 585 590 Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys LeuVal Lys Thr Asn 595 600 605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro SerAsp Ser Ile Tyr Ile 610 615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val ProPhe Asp Asn Asp Leu Arg 625 630 635 640 Cys Lys Val Ser Leu Gly Ser TyrPro Phe 645 650 80 1968 DNA Caenorhabditis elegans 80 atgagggaaatgccggacag tcccaagttt gcgttagtca cgtttgttgt gtatgcagtg 60 gttttgtacaatgtcaacag cgttttctgg aaatttgtat tcatcggata tgttgtattt 120 aggctgcttcgcactgattt tggaagaaga gcacttgcca cgttacctag agattttgcg 180 ggactgaagctcttaatatc ggttaagtcg acaattcgtg gcttgttcaa gaaagatcgc 240 ccaattcatgaaatcttttt gaatcaggtg aaacagcatc caaacaaagt ggcgattatt 300 gaaattgaaagtggtaggca gttgacgtat caagaattga atgcgttagc taatcagtat 360 gctaacctttacgtgagtga aggttacaaa atgggcgacg ttgtcgcttt gtttatggaa 420 aatagcatcgacttctttgc aatttggctg ggactttcca agattggagt cgtgtcggcg 480 ttcatcaactcaaacttgaa gttggagcca ttggcacatt cgattaatgt ttcgaagtgc 540 aaatcatgcattaccaatat caatctgttg ccgatgttca aagccgctcg tgaaaagaat 600 ctgatcagtgacgagatcca cgtgtttctg gctggaactc aggttgatgg acgtcataga 660 agtcttcagcaagatctcca tcttttctct gaggatgaac ctccagttat agacggactc 720 aattttagaagcgttctgtg ttatatttac acttccggta ctaccggaaa tccaaagcca 780 gccgtcattaaacacttccg ttacttctgg attgcgatgg gagcaggaaa agcatttgga 840 attaataagtcagacgttgt gtacattacg atgccaatgt atcactctgc cgccggtatc 900 atgggtattggatcattaat tgcattcggg tcgaccgctg ttattaggaa aaagttttcg 960 gcaagcaacttctggaaaga ttgcgtcaag tacaacgtca cagcgacaca gtacattgga 1020 gaaatctgcaggtatcttct ggcagcgaat ccatgtcctg aagagaaaca acacaacgtg 1080 cgattgatgtggggaaatgg tttgagagga caaatttgga aagagtttgt aggaagattt 1140 ggaattaagaaaattggaga gttgtacggc tcaacagaag gaaactccaa tattgttaac 1200 gtggataaccatgttggagc ttgtggattc atgccaattt atccccatat tggatccctc 1260 tacccagttcgacttattaa ggttgataga gccactggag agcttgaacg tgataagaac 1320 ggactctgtgtgccgtgtgt gcctggtgaa actggggaaa tggttggcgt tatcaaggag 1380 aaagatattcttctaaagtt cgaaggatat gtcagcgaag gggatactgc aaagaaaatc 1440 tacagagatgtgttcaagca tggagataag gtgtttgcaa gtggagatat tcttcattgg 1500 gatgatcttggatacttgta ctttgtggac cgttgtggag acactttccg ttggaaaggg 1560 gagaacgtgtcaactactga agttgaggga attcttcagc ctgtgatgga tgtggaagat 1620 gcaactgtttatggagtcac tgtcggtaaa atggaggggc gtgccggaat ggctggtatt 1680 gtcgtcaaggatggaacgga tgttgagaaa ttcatcgccg atattacttc tcgactgacc 1740 gaaaatctggcgtcttacgc aatccctgtt ttcattcggc tgtgcaagga agttgatcga 1800 accggaaccttcaaactcaa gaagactgat cttcaaaaac aaggttacga cctggttgct 1860 tgtaaaggagacccaattta ctactggtca gctgcagaaa aatcctacaa accactgact 1920 gacaaaatgcaacaggatat tgacactggt gtttatgatc gcatttaa 1968 81 655 PRT Caenorhabditiselegans 81 Met Arg Glu Met Pro Asp Ser Pro Lys Phe Ala Leu Val Thr PheVal 1 5 10 15 Val Tyr Ala Val Val Leu Tyr Asn Val Asn Ser Val Phe TrpLys Phe 20 25 30 Val Phe Ile Gly Tyr Val Val Phe Arg Leu Leu Arg Thr AspPhe Gly 35 40 45 Arg Arg Ala Leu Ala Thr Leu Pro Arg Asp Phe Ala Gly LeuLys Leu 50 55 60 Leu Ile Ser Val Lys Ser Thr Ile Arg Gly Leu Phe Lys LysAsp Arg 65 70 75 80 Pro Ile His Glu Ile Phe Leu Asn Gln Val Lys Gln HisPro Asn Lys 85 90 95 Val Ala Ile Ile Glu Ile Glu Ser Gly Arg Gln Leu ThrTyr Gln Glu 100 105 110 Leu Asn Ala Leu Ala Asn Gln Tyr Ala Asn Leu TyrVal Ser Glu Gly 115 120 125 Tyr Lys Met Gly Asp Val Val Ala Leu Phe MetGlu Asn Ser Ile Asp 130 135 140 Phe Phe Ala Ile Trp Leu Gly Leu Ser LysIle Gly Val Val Ser Ala 145 150 155 160 Phe Ile Asn Ser Asn Leu Lys LeuGlu Pro Leu Ala His Ser Ile Asn 165 170 175 Val Ser Lys Cys Lys Ser CysIle Thr Asn Ile Asn Leu Leu Pro Met 180 185 190 Phe Lys Ala Ala Arg GluLys Asn Leu Ile Ser Asp Glu Ile His Val 195 200 205 Phe Leu Ala Gly ThrGln Val Asp Gly Arg His Arg Ser Leu Gln Gln 210 215 220 Asp Leu His LeuPhe Ser Glu Asp Glu Pro Pro Val Ile Asp Gly Leu 225 230 235 240 Asn PheArg Ser Val Leu Cys Tyr Ile Tyr Thr Ser Gly Thr Thr Gly 245 250 255 AsnPro Lys Pro Ala Val Ile Lys His Phe Arg Tyr Phe Trp Ile Ala 260 265 270Met Gly Ala Gly Lys Ala Phe Gly Ile Asn Lys Ser Asp Val Val Tyr 275 280285 Ile Thr Met Pro Met Tyr His Ser Ala Ala Gly Ile Met Gly Ile Gly 290295 300 Ser Leu Ile Ala Phe Gly Ser Thr Ala Val Ile Arg Lys Lys Phe Ser305 310 315 320 Ala Ser Asn Phe Trp Lys Asp Cys Val Lys Tyr Asn Val ThrAla Thr 325 330 335 Gln Tyr Ile Gly Glu Ile Cys Arg Tyr Leu Leu Ala AlaAsn Pro Cys 340 345 350 Pro Glu Glu Lys Gln His Asn Val Arg Leu Met TrpGly Asn Gly Leu 355 360 365 Arg Gly Gln Ile Trp Lys Glu Phe Val Gly ArgPhe Gly Ile Lys Lys 370 375 380 Ile Gly Glu Leu Tyr Gly Ser Thr Glu GlyAsn Ser Asn Ile Val Asn 385 390 395 400 Val Asp Asn His Val Gly Ala CysGly Phe Met Pro Ile Tyr Pro His 405 410 415 Ile Gly Ser Leu Tyr Pro ValArg Leu Ile Lys Val Asp Arg Ala Thr 420 425 430 Gly Glu Leu Glu Arg AspLys Asn Gly Leu Cys Val Pro Cys Val Pro 435 440 445 Gly Glu Thr Gly GluMet Val Gly Val Ile Lys Glu Lys Asp Ile Leu 450 455 460 Leu Lys Phe GluGly Tyr Val Ser Glu Gly Asp Thr Ala Lys Lys Ile 465 470 475 480 Tyr ArgAsp Val Phe Lys His Gly Asp Lys Val Phe Ala Ser Gly Asp 485 490 495 IleLeu His Trp Asp Asp Leu Gly Tyr Leu Tyr Phe Val Asp Arg Cys 500 505 510Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 515 520525 Glu Gly Ile Leu Gln Pro Val Met Asp Val Glu Asp Ala Thr Val Tyr 530535 540 Gly Val Thr Val Gly Lys Met Glu Gly Arg Ala Gly Met Ala Gly Ile545 550 555 560 Val Val Lys Asp Gly Thr Asp Val Glu Lys Phe Ile Ala AspIle Thr 565 570 575 Ser Arg Leu Thr Glu Asn Leu Ala Ser Tyr Ala Ile ProVal Phe Ile 580 585 590 Arg Leu Cys Lys Glu Val Asp Arg Thr Gly Thr PheLys Leu Lys Lys 595 600 605 Thr Asp Leu Gln Lys Gln Gly Tyr Asp Leu ValAla Cys Lys Gly Asp 610 615 620 Pro Ile Tyr Tyr Trp Ser Ala Ala Glu LysSer Tyr Lys Pro Leu Thr 625 630 635 640 Asp Lys Met Gln Gln Asp Ile AspThr Gly Val Tyr Asp Arg Ile 645 650 655 82 1932 DNA Cochlioboluheterostrophus 82 atggcgtgta tgcatcaggc tcagctatac aatgatctag aggaattgctaactggtcca 60 tcagtaccca tcgttgctgg agctgctgga gctgcagctc tcactgcctacattaacgcc 120 aaataccaca tagcccatga tctcaagacc ctcggtggtg gattgacacaatcgtccgaa 180 gcgattgatt tcataaaccg ccgcgtcgca caaaagcgcg tcctcacgcaccacatcttc 240 caggagcagg tccaaaaaca atcaaatcat ccctttctta tctttgagggcaagacatgg 300 tcttacaagg agttctctga ggcatacacg agggtcgcga actggctgattgatgagctg 360 gacgtacaag taggggagat ggtcgcaatt gatggcggaa atagtgcagagcacctgatg 420 ctttggcttg cacttgatgc aatcggtgcg gctacgagtt ttttgaactggaacctgaca 480 ggggcagggt taattcattg cataaagcta tgcgaatgtc gattcgttatcgcagacatc 540 gatattaaag cgaacattga accgtgccgt ggcgaactgg aggagacgggcatcaacatt 600 cactactatg acccatcctt catctcatcg ctaccgaata acacgccaattcccgacagc 660 cgcactgaga acattgaatt agattcagta cgaggactga tatacacatctggaaccact 720 ggtctaccta aaggcgtgtt tataagcact ggccgcgagc ttaggactgactggtcgatt 780 tcaaagtatc taaatctcaa gcccacggat cgaatgtata catgtatgccgctctaccat 840 gccgctgcac acagcctctg tacagcatca gttattcatg gtggaggtaccgtggtattg 900 agcaggaaat tctcacacaa gaagttctgg cctgaagttg tggcttcggaagcaaatatc 960 attcagtacg ttggtgaatt aggtcgatat ctcctgaatg gtccaaagagtccttacgac 1020 agggcccata aagtccagat ggcgtggggc aatggcatgc gtccagacgtgtgggaagcg 1080 tttcgtgaac gcttcaacat accaattatt catgagctct atgccgcaaccgatgggctc 1140 gggtcaatga ccaatcgtaa cgcgggccct tttacagcaa actgtattgcgctgcgaggg 1200 ctgatctggc actggaaatt tcgaaatcag gaagtgctgg tcaagatggatctcgatact 1260 gatgagatca tgagagatcg caatgggttt gcgatacgat gcgctgtcaatgaacctgga 1320 cagatgcttt ttcggctgac acccgaaact ctggctggtg caccaagctactacaacaac 1380 gaaacggcca cacagagcag gcggattaca gatgtgtttc aaaagggtgacctgtggttc 1440 aagtccggtg acatgctacg gcaagacgcc gaaggccgcg tctactttgtcgatcgacta 1500 ggcgatacgt tccgctggaa atccgaaaac gtttctacca atgaagtcgcggacgtgatg 1560 ggcacatttc ctcagattgc tgaaacgaat gtatacggtg tccttgtgccgggtaacgat 1620 ggtcgagtgc gcagcctcaa ttgtcatggc agacggcgtg acagagtcgacattcgcttc 1680 gctgcccttg caaagcacgc ccgagatcgg ttaccgggtt atgctgtaccactgtttctg 1740 agggtaactc cagcacttga atatacgggc acattaaaga ttcagaaaggacgcctcaag 1800 caggaaggta tagacccaga taagatttcc ggcgaagata agttatactggctgccgcct 1860 ggtagcgata tatatttacc atttggaaag atggagtggc agggaattgtagataagcgt 1920 atacggctgt ga 1932 83 643 PRT Cochliobolu heterostrophus83 Met Ala Cys Met His Gln Ala Gln Leu Tyr Asn Asp Leu Glu Glu Leu 1 510 15 Leu Thr Gly Pro Ser Val Pro Ile Val Ala Gly Ala Ala Gly Ala Ala 2025 30 Ala Leu Thr Ala Tyr Ile Asn Ala Lys Tyr His Ile Ala His Asp Leu 3540 45 Lys Thr Leu Gly Gly Gly Leu Thr Gln Ser Ser Glu Ala Ile Asp Phe 5055 60 Ile Asn Arg Arg Val Ala Gln Lys Arg Val Leu Thr His His Ile Phe 6570 75 80 Gln Glu Gln Val Gln Lys Gln Ser Asn His Pro Phe Leu Ile Phe Glu85 90 95 Gly Lys Thr Trp Ser Tyr Lys Glu Phe Ser Glu Ala Tyr Thr Arg Val100 105 110 Ala Asn Trp Leu Ile Asp Glu Leu Asp Val Gln Val Gly Glu MetVal 115 120 125 Ala Ile Asp Gly Gly Asn Ser Ala Glu His Leu Met Leu TrpLeu Ala 130 135 140 Leu Asp Ala Ile Gly Ala Ala Thr Ser Phe Leu Asn TrpAsn Leu Thr 145 150 155 160 Gly Ala Gly Leu Ile His Cys Ile Lys Leu CysGlu Cys Arg Phe Val 165 170 175 Ile Ala Asp Ile Asp Ile Lys Ala Asn IleGlu Pro Cys Arg Gly Glu 180 185 190 Leu Glu Glu Thr Gly Ile Asn Ile HisTyr Tyr Asp Pro Ser Phe Ile 195 200 205 Ser Ser Leu Pro Asn Asn Thr ProIle Pro Asp Ser Arg Thr Glu Asn 210 215 220 Ile Glu Leu Asp Ser Val ArgGly Leu Ile Tyr Thr Ser Gly Thr Thr 225 230 235 240 Gly Leu Pro Lys GlyVal Phe Ile Ser Thr Gly Arg Glu Leu Arg Thr 245 250 255 Asp Trp Ser IleSer Lys Tyr Leu Asn Leu Lys Pro Thr Asp Arg Met 260 265 270 Tyr Thr CysMet Pro Leu Tyr His Ala Ala Ala His Ser Leu Cys Thr 275 280 285 Ala SerVal Ile His Gly Gly Gly Thr Val Val Leu Ser Arg Lys Phe 290 295 300 SerHis Lys Lys Phe Trp Pro Glu Val Val Ala Ser Glu Ala Asn Ile 305 310 315320 Ile Gln Tyr Val Gly Glu Leu Gly Arg Tyr Leu Leu Asn Gly Pro Lys 325330 335 Ser Pro Tyr Asp Arg Ala His Lys Val Gln Met Ala Trp Gly Asn Gly340 345 350 Met Arg Pro Asp Val Trp Glu Ala Phe Arg Glu Arg Phe Asn IlePro 355 360 365 Ile Ile His Glu Leu Tyr Ala Ala Thr Asp Gly Leu Gly SerMet Thr 370 375 380 Asn Arg Asn Ala Gly Pro Phe Thr Ala Asn Cys Ile AlaLeu Arg Gly 385 390 395 400 Leu Ile Trp His Trp Lys Phe Arg Asn Gln GluVal Leu Val Lys Met 405 410 415 Asp Leu Asp Thr Asp Glu Ile Met Arg AspArg Asn Gly Phe Ala Ile 420 425 430 Arg Cys Ala Val Asn Glu Pro Gly GlnMet Leu Phe Arg Leu Thr Pro 435 440 445 Glu Thr Leu Ala Gly Ala Pro SerTyr Tyr Asn Asn Glu Thr Ala Thr 450 455 460 Gln Ser Arg Arg Ile Thr AspVal Phe Gln Lys Gly Asp Leu Trp Phe 465 470 475 480 Lys Ser Gly Asp MetLeu Arg Gln Asp Ala Glu Gly Arg Val Tyr Phe 485 490 495 Val Asp Arg LeuGly Asp Thr Phe Arg Trp Lys Ser Glu Asn Val Ser 500 505 510 Thr Asn GluVal Ala Asp Val Met Gly Thr Phe Pro Gln Ile Ala Glu 515 520 525 Thr AsnVal Tyr Gly Val Leu Val Pro Gly Asn Asp Gly Arg Val Arg 530 535 540 SerLeu Asn Cys His Gly Arg Arg Arg Asp Arg Val Asp Ile Arg Phe 545 550 555560 Ala Ala Leu Ala Lys His Ala Arg Asp Arg Leu Pro Gly Tyr Ala Val 565570 575 Pro Leu Phe Leu Arg Val Thr Pro Ala Leu Glu Tyr Thr Gly Thr Leu580 585 590 Lys Ile Gln Lys Gly Arg Leu Lys Gln Glu Gly Ile Asp Pro AspLys 595 600 605 Ile Ser Gly Glu Asp Lys Leu Tyr Trp Leu Pro Pro Gly SerAsp Ile 610 615 620 Tyr Leu Pro Phe Gly Lys Met Glu Trp Gln Gly Ile ValAsp Lys Arg 625 630 635 640 Ile Arg Leu 84 597 DNA Aspergillus nidulans84 ctttaccatt catcagcttc attctgcatt tttagcttga cggcagccgg gtctacgctg 60atcatcggcc gcaagttctc cgcgagaaac ttcataaagg aagcgcgcga gaacgacgcc 120acggtcatcc agtacgtggg tgagaccttg cgatatctgc tcgccacccc cggtgaaacc 180gatccagtta ctggcgaaga cctggacaaa aagcacaata ttcgagcagt atacggcaac 240gggctacggc cggatatctg gaaccgcttc aaggagcgct tcaacgtgcc gacggttgcc 300gaattttatg ctgcaaccga gagcccaggc ggaacatgga actattcaac aaatgacttc 360actgccggag ccattgggca cactggcgtg cttagtggat ggcttcttgg acgcggcctt 420actattgtcg aggtggacca ggaatcacag gaaccatggc gcgatcccca aaccgggttc 480tgcaagccgg tcccgcgagg cgaagcaggc gagctcctgt atgccattga tccggccgac 540ccgggcgaga ccttccaggg ctactaccgc aactccttta gagcacactg gcggccg 597 85199 PRT Aspergillus nidulans 85 Leu Tyr His Ser Ser Ala Ser Phe Cys IlePhe Ser Leu Thr Ala Ala 1 5 10 15 Gly Ser Thr Leu Ile Ile Gly Arg LysPhe Ser Ala Arg Asn Phe Ile 20 25 30 Lys Glu Ala Arg Glu Asn Asp Ala ThrVal Ile Gln Tyr Val Gly Glu 35 40 45 Thr Leu Arg Tyr Leu Leu Ala Thr ProGly Glu Thr Asp Pro Val Thr 50 55 60 Gly Glu Asp Leu Asp Lys Lys His AsnIle Arg Ala Val Tyr Gly Asn 65 70 75 80 Gly Leu Arg Pro Asp Ile Trp AsnArg Phe Lys Glu Arg Phe Asn Val 85 90 95 Pro Thr Val Ala Glu Phe Tyr AlaAla Thr Glu Ser Pro Gly Gly Thr 100 105 110 Trp Asn Tyr Ser Thr Asn AspPhe Thr Ala Gly Ala Ile Gly His Thr 115 120 125 Gly Val Leu Ser Gly TrpLeu Leu Gly Arg Gly Leu Thr Ile Val Glu 130 135 140 Val Asp Gln Glu SerGln Glu Pro Trp Arg Asp Pro Gln Thr Gly Phe 145 150 155 160 Cys Lys ProVal Pro Arg Gly Glu Ala Gly Glu Leu Leu Tyr Ala Ile 165 170 175 Asp ProAla Asp Pro Gly Glu Thr Phe Gln Gly Tyr Tyr Arg Asn Ser 180 185 190 PheArg Ala His Trp Arg Pro 195 86 522 DNA Magnaporthe grisea misc_feature(1)...(522) n = A,T,C or G 86 gcaaaggccg acgcgtggct gcggacgggtaacgtgatca gggcggacaa cgaagggcga 60 ctcttcttcc acgaccggat cggagacacgttccgatgga agggagagac ngtcagcaca 120 caagaggtca gtttggtgct cggacgacacgactcaatca aggaggccaa cgtgtacggc 180 gtgacggtgc cgaaccacga cgggcgggccggctgcgctg cgctcacgct atcagacgct 240 ctggcgactg aaaagaagct gggcgatgagctgctaaagg gattggctac tcactcgtcg 300 acttcgcttc ccaagtttgc ggtgccgcagttcctacggg tggtgcgcgg cgagatgcag 360 tcaacgggca ccaacaagca acagaagcacgacctgaggg tgcagggtgt agagccgggc 420 aaggtgggcg tagacgaggt gtactggttgcggggaggga catatgtacc attcggaaca 480 gaggattggg atgggttgaa gaagggtcttgtgaagttgt ga 522 87 173 PRT Magnaporthe grisea 87 Ala Lys Ala Asp AlaTrp Leu Arg Thr Gly Asn Val Ile Arg Ala Asp 1 5 10 15 Asn Glu Gly ArgLeu Phe Phe His Asp Arg Ile Gly Asp Thr Phe Arg 20 25 30 Trp Lys Gly GluThr Val Ser Thr Gln Glu Val Ser Leu Val Leu Gly 35 40 45 Arg His Asp SerIle Lys Glu Ala Asn Val Tyr Gly Val Thr Val Pro 50 55 60 Asn His Asp GlyArg Ala Gly Cys Ala Ala Leu Thr Leu Ser Asp Ala 65 70 75 80 Leu Ala ThrGlu Lys Lys Leu Gly Asp Glu Leu Leu Lys Gly Leu Ala 85 90 95 Thr His SerSer Thr Ser Leu Pro Lys Phe Ala Val Pro Gln Phe Leu 100 105 110 Arg ValVal Arg Gly Glu Met Gln Ser Thr Gly Thr Asn Lys Gln Gln 115 120 125 LysHis Asp Leu Arg Val Gln Gly Val Glu Pro Gly Lys Val Gly Val 130 135 140Asp Glu Val Tyr Trp Leu Arg Gly Gly Thr Tyr Val Pro Phe Gly Thr 145 150155 160 Glu Asp Trp Asp Gly Leu Lys Lys Gly Leu Val Lys Leu 165 170 881872 DNA Saccharomyces cerevisiae 88 atgtctccca tacaggttgt tgtctttgccttgtcaagga ttttcctgct attattcaga 60 cttatcaagc taattataac ccctatccagaaatcactgg gttatctatt tggtaattat 120 tttgatgaat tagaccgtaa atatagatacaaggaggatt ggtatattat tccttacttt 180 ttgaaaagcg tgttttgtta tatcattgatgtgagaagac ataggtttca aaactggtac 240 ttatttatta aacaggtcca acaaaatggtgaccatttag cgattagtta cacccgtccc 300 atggccgaaa agggagaatt tcaactcgaaacctttacgt atattgaaac ttataacata 360 gtgttgagat tgtctcatat tttgcattttgattataacg ttcaggccgg tgactacgtg 420 gcaatcgatt gtactaataa acctcttttcgtatttttat ggctttcttt gtggaacatt 480 ggggctattc cagctttttt aaactataatactaaaggca ctccgctggt tcactcccta 540 aagatttcca atattacgca ggtatttattgaccctgatg ccagtaatcc gatcagagaa 600 tcggaagaag aaatcaaaaa cgcacttcctgatgttaaat taaactatct tgaagaacaa 660 gacttaatgc atgaactttt aaattcgcaatcaccggaat tcttacaaca agacaacgtt 720 aggacaccac taggcttgac cgattttaaaccctctatgt taatttatac atctggaacc 780 actggtttgc ctaaatccgc tattatgtcttggagaaaat cctccgtagg ttgtcaagtt 840 tttggtcatg ttttacatat gactaatgaaagcactgtgt tcacagccat gccattgttc 900 cattcaactg ctgccttatt aggtgcgtgcgccattctat ctcacggtgg ttgccttgcg 960 ttatcgcata aattttctgc cagtacattttggaagcaag tttatttaac aggagccacg 1020 cacatccaat atgtcggaga agtctgtagatacctgttac atacgccaat ttctaagtat 1080 gaaaagatgc ataaggtgaa ggttgcttatggtaacgggc tgagacctga catctggcag 1140 gacttcagga agaggttcaa catagaagttattggtgaat tctatgccgc aactgaagct 1200 ccttttgcta caactacctt ccagaaaggtgactttggaa ttggcgcatg taggaactat 1260 ggtactataa ttcaatggtt tttgtcattccaacaaacat tggtaaggat ggacccaaat 1320 gacgattccg ttatatatag aaattccaagggtttctgcg aagtggcccc tgttggcgaa 1380 ccaggagaaa tgttaatgag aatctttttccctaaaaaac cagaaacatc ttttcaaggt 1440 tatcttggta atgccaagga aacaaagtccaaagttgtga gggatgtctt cagacgtggc 1500 gatgcttggt atagatgtgg agatttattaaaagcggacg aatatggatt atggtatttc 1560 cttgatagaa tgggtgatac tttcagatggaaatctgaaa atgtttccac tactgaagta 1620 gaagatcagt tgacggccag taacaaagaacaatatgcac aagttctagt tgttggtatt 1680 aaagtaccta aatatgaagg tagagctggttttgcagtta ttaaactaac tgacaactct 1740 cttgacatca ctgcaaagac caaattattaaatgattcct tgagccggtt aaatctaccg 1800 tcttatgcta tgcccctatt tgttaaatttgttgatgaaa ttaaaatgac agataacctc 1860 ataaaatttt ga 1872 89 623 PRTSaccharomyces cerevisiae 89 Met Ser Pro Ile Gln Val Val Val Phe Ala LeuSer Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu Ile Lys Leu Ile IleThr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe Gly Asn Tyr Phe AspGlu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp Trp Tyr Ile Ile ProTyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile Asp Val Arg Arg HisArg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys Gln Val Gln Gln AsnGly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro Met Ala Glu Lys GlyGlu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile Glu Thr Tyr Asn IleVal Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe Asp Tyr Asn Val GlnAla Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr Asn Lys Pro Leu PheVal Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160 Gly Ala Ile ProAla Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170 175 Val His SerLeu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180 185 190 Asp AlaSer Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala 195 200 205 LeuPro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu Met His 210 215 220Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln Asp Asn Val 225 230235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro Ser Met Leu Ile Tyr245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile Met Ser TrpArg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe Gly His Val Leu HisMet Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala Met Pro Leu Phe HisSer Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala Ile Leu Ser His GlyGly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe Ser Ala Ser Thr PheTrp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr His Ile Gln Tyr ValGly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr Pro Ile Ser Lys TyrGlu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr Gly Asn Gly Leu ArgPro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg Phe Asn Ile Glu ValIle Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400 Pro Phe Ala ThrThr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410 415 Cys Arg AsnTyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420 425 430 Thr LeuVal Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn 435 440 445 SerLys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly Glu Met 450 455 460Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser Phe Gln Gly 465 470475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val Arg Asp Val485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp Leu Leu LysAla 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg Met Gly AspThr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser Thr Thr Glu Val GluAsp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln Tyr Ala Gln Val LeuVal Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr Glu Gly Arg Ala GlyPhe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser Leu Asp Ile Thr AlaLys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser Arg Leu Asn Leu ProSer Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe Val Asp Glu Ile LysMet Thr Asp Asn Leu Ile Lys Phe 610 615 620 90 1794 DNA Mycobacteriumtuberculosis 90 gtgtccgatt actacggcgg cgcacacaca acggtcaggc tgatcgacctggcaactcgg 60 atgccgcgag tgttggcgga cacgccggtg attgtgcgtg gggcaatgaccgggctgctg 120 gcccggccga attccaaggc gtcgatcggc acggtgttcc aggaccgggccgctcgctac 180 ggtgaccgag tcttcctgaa attcggcgat cagcagctga cctaccgcgacgctaacgcc 240 accgccaacc ggtacgccgc ggtgttggcc gcccgcggcg tcggccccggcgacgtcgtt 300 ggcatcatgt tgcgtaactc acccagcaca gtcttggcga tgctggccacggtcaagtgc 360 ggcgctatcg ccggcatgct caactaccac cagcgcggcg aggtgttggcgcacagcctg 420 ggtctgctgg acgcgaaggt actgatcgca gagtccgact tggtcagcgccgtcgccgaa 480 tgcggcgcct cgcgcggccg ggtagcgggc gacgtgctga ccgtcgaggacgtggagcga 540 ttcgccacaa cggcgcccgc caccaacccg gcgtcggcgt cggcggtgcaagccaaagac 600 accgcgttct acatcttcac ctcgggcacc accggatttc ccaaggccagtgtcatgacg 660 catcatcggt ggctgcgggc gctggccgtc ttcggaggga tggggctgcggctgaagggt 720 tccgacacgc tctacagctg cctgccgctg taccacaaca acgcgttaacggtcgcggtg 780 tcgtcggtga tcaattctgg ggcgaccctg gcgctgggta agtcgttttcggcgtcgcgg 840 ttctgggatg aggtgattgc caaccgggcg acggcgttcg tctacatcggcgaaatctgc 900 cgttatctgc tcaaccagcc ggccaagccg accgaccgtg cccaccaggtgcgggtgatc 960 tgcggtaacg ggctgcggcc ggagatctgg gatgagttca ccacccgcttcggggtcgcg 1020 cgggtgtgcg agttctacgc cgccagcgaa ggcaactcgg cctttatcaacatcttcaac 1080 gtgcccagga ccgccggggt atcgccgatg ccgcttgcct ttgtggaatacgacctggac 1140 accggcgatc cgctgcggga tgcgagcggg cgagtgcgtc gggtacccgacggtgaaccc 1200 ggcctgttgc ttagccgggt caaccggctg cagccgttcg acggctacaccgacccggtt 1260 gccagcgaaa agaagttggt gcgcaacgct tttcgagatg gcgactgttggttcaacacc 1320 ggtgacgtga tgagcccgca gggcatgggc catgccgcct tcgtcgatcggctgggcgac 1380 accttccgct ggaagggcga gaatgtcgcc accactcagg tcgaagcggcactggcctcc 1440 gaccagaccg tcgaggagtg cacggtctac ggcgtccaga ttccgcgcaccggcgggcgc 1500 gccggaatgg ccgcgatcac actgcgcgct ggcgccgaat tcgacggccaggcgctggcc 1560 cgaacggttt acggtcactt gcccggctat gcacttccgc tctttgttcgggtagtgggg 1620 tcgctggcgc acaccacgac gttcaagagt cgcaaggtgg agttgcgcaaccaggcctat 1680 ggcgccgaca tcgaggatcc gctgtacgta ctggccggcc cggacgaaggatatgtgccg 1740 tactacgccg aataccctga ggaggtttcg ctcggaaggc gaccgcagggctag 1794 91 597 PRT Mycobacterium tuberculosis 91 Met Ser Asp Tyr TyrGly Gly Ala His Thr Thr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr ArgMet Pro Arg Val Leu Ala Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala MetThr Gly Leu Leu Ala Arg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr ValPhe Gln Asp Arg Ala Ala Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys PheGly Asp Gln Gln Leu Thr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala AsnArg Tyr Ala Ala Val Leu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp ValVal Gly Ile Met Leu Arg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala MetLeu Ala Thr Val Lys Cys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 TyrHis Gln Arg Gly Glu Val Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140Ala Lys Val Leu Ile Ala Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150155 160 Cys Gly Ala Ser Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu165 170 175 Asp Val Glu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro AlaSer 180 185 190 Ala Ser Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile PheThr Ser 195 200 205 Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr HisHis Arg Trp 210 215 220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly LeuArg Leu Lys Gly 225 230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro LeuTyr His Asn Asn Ala Leu 245 250 255 Thr Val Ala Val Ser Ser Val Ile AsnSer Gly Ala Thr Leu Ala Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser ArgPhe Trp Asp Glu Val Ile Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val TyrIle Gly Glu Ile Cys Arg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys ProThr Asp Arg Ala His Gln Val Arg Val Ile 305 310 315 320 Cys Gly Asn GlyLeu Arg Pro Glu Ile Trp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly ValAla Arg Val Cys Glu Phe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser AlaPhe Ile Asn Ile Phe Asn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 ProMet Pro Leu Ala Phe Val Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380Leu Arg Asp Ala Ser Gly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390395 400 Gly Leu Leu Leu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr405 410 415 Thr Asp Pro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala PheArg 420 425 430 Asp Gly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser ProGln Gly 435 440 445 Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp ThrPhe Arg Trp 450 455 460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu AlaAla Leu Ala Ser 465 470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val TyrGly Val Gln Ile Pro Arg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala AlaIle Thr Leu Arg Ala Gly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu AlaArg Thr Val Tyr Gly His Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu PheVal Arg Val Val Gly Ser Leu Ala His 530 535 540 Thr Thr Thr Phe Lys SerArg Lys Val Glu Leu Arg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp IleGlu Asp Pro Leu Tyr Val Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr ValPro Tyr Tyr Ala Glu Tyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg ArgPro Gln Gly 595 92 646 PRT Mus musculus 92 Met Arg Ala Pro Gly Ala GlyThr Ala Ser Val Ala Ser Leu Ala Leu 1 5 10 15 Leu Trp Phe Leu Gly LeuPro Trp Thr Trp Ser Ala Ala Ala Ala Phe 20 25 30 Cys Val Tyr Val Gly GlyGly Gly Trp Arg Phe Leu Arg Ile Val Cys 35 40 45 Lys Thr Ala Arg Arg AspLeu Phe Gly Leu Ser Val Leu Ile Arg Val 50 55 60 Arg Leu Glu Leu Arg ArgHis Arg Arg Ala Gly Asp Thr Ile Pro Cys 65 70 75 80 Ile Phe Gln Ala ValAla Arg Arg Gln Pro Glu Arg Leu Ala Leu Val 85 90 95 Asp Ala Ser Ser GlyIle Cys Trp Thr Phe Ala Gln Leu Asp Thr Tyr 100 105 110 Ser Asn Ala ValAla Asn Leu Phe Arg Gln Leu Gly Phe Ala Pro Gly 115 120 125 Asp Val ValAla Val Phe Leu Glu Gly Arg Pro Glu Phe Val Gly Leu 130 135 140 Trp LeuGly Leu Ala Lys Ala Gly Val Val Ala Ala Leu Leu Asn Val 145 150 155 160Asn Leu Arg Arg Glu Pro Leu Ala Phe Cys Leu Gly Thr Ser Ala Ala 165 170175 Lys Ala Leu Ile Tyr Gly Gly Glu Met Ala Ala Ala Val Ala Glu Val 180185 190 Ser Glu Gln Leu Gly Lys Ser Leu Leu Lys Phe Cys Ser Gly Asp Leu195 200 205 Gly Pro Glu Ser Ile Leu Pro Asp Thr Gln Leu Leu Asp Pro MetLeu 210 215 220 Ala Glu Ala Pro Thr Thr Pro Leu Ala Gln Ala Pro Gly LysGly Met 225 230 235 240 Asp Asp Arg Leu Phe Tyr Ile Tyr Thr Ser Gly ThrThr Gly Leu Pro 245 250 255 Lys Ala Ala Ile Val Val His Ser Arg Tyr TyrArg Ile Ala Ala Phe 260 265 270 Gly His His Ser Tyr Ser Met Arg Ala AlaAsp Val Leu Tyr Asp Cys 275 280 285 Leu Pro Leu Tyr His Ser Ala Gly AsnIle Met Gly Val Gly Gln Cys 290 295 300 Val Ile Tyr Gly Leu Thr Val ValLeu Arg Lys Lys Phe Ser Ala Ser 305 310 315 320 Arg Phe Trp Asp Asp CysVal Lys Tyr Asn Cys Thr Val Val Gln Tyr 325 330 335 Ile Gly Glu Ile CysArg Tyr Leu Leu Arg Gln Pro Val Arg Asp Val 340 345 350 Glu Gln Arg HisArg Val Arg Leu Ala Val Gly Asn Gly Leu Arg Pro 355 360 365 Ala Ile TrpGlu Glu Phe Thr Gln Arg Phe Gly Val Pro Gln Ile Gly 370 375 380 Glu PheTyr Gly Ala Thr Glu Cys Asn Cys Ser Ile Ala Asn Met Asp 385 390 395 400Gly Lys Val Gly Ser Cys Gly Phe Asn Ser Arg Ile Leu Thr His Val 405 410415 Tyr Pro Ile Arg Leu Val Lys Val Asn Glu Asp Thr Met Glu Pro Leu 420425 430 Arg Asp Ser Glu Gly Leu Cys Ile Pro Cys Gln Pro Gly Glu Pro Gly435 440 445 Leu Leu Val Gly Gln Ile Asn Gln Gln Asp Pro Leu Arg Arg PheAsp 450 455 460 Gly Tyr Val Ser Asp Ser Ala Thr Asn Lys Lys Ile Ala HisSer Val 465 470 475 480 Phe Arg Lys Gly Asp Ser Ala Tyr Leu Ser Gly AspVal Leu Val Met 485 490 495 Asp Glu Leu Gly Tyr Met Tyr Phe Arg Asp ArgSer Gly Asp Thr Phe 500 505 510 Arg Trp Arg Gly Glu Asn Val Ser Thr ThrGlu Val Glu Ala Val Leu 515 520 525 Ser Arg Leu Leu Gly Gln Thr Asp ValAla Val Tyr Gly Val Ala Val 530 535 540 Pro Gly Val Glu Gly Lys Ala GlyMet Ala Ala Ile Ala Asp Pro His 545 550 555 560 Ser Gln Leu Asp Pro AsnSer Met Tyr Gln Glu Leu Gln Lys Val Leu 565 570 575 Ala Ser Tyr Ala ArgPro Ile Phe Leu Arg Leu Leu Pro Gln Val Asp 580 585 590 Thr Thr Gly ThrPhe Lys Ile Gln Lys Thr Arg Leu Gln Arg Glu Gly 595 600 605 Phe Asp ProArg Gln Thr Ser Asp Arg Leu Phe Phe Leu Asp Leu Lys 610 615 620 Gln GlyArg Tyr Leu Pro Leu Asp Glu Arg Val His Ala Arg Ile Cys 625 630 635 640Ala Gly Asp Phe Ser Leu 645 93 620 PRT Mus musculus VARIANT (1)...(620)Xaa = Any Amino Acid 93 Met Leu Pro Val Leu Tyr Thr Gly Leu Ala Gly LeuLeu Leu Leu Pro 1 5 10 15 Leu Leu Leu Thr Cys Cys Cys Pro Tyr Leu LeuGln Asp Val Arg Tyr 20 25 30 Phe Leu Arg Leu Ala Asn Met Ala Arg Arg ValArg Ser Tyr Arg Gln 35 40 45 Arg Arg Pro Val Arg Thr Ile Leu Arg Ala PheLeu Glu Gln Ala Arg 50 55 60 Lys Thr Pro His Lys Pro Phe Leu Leu Phe ArgAsp Glu Thr Leu Thr 65 70 75 80 Tyr Ala Gln Val Asp Arg Arg Ser Asn GlnVal Ala Arg Ala Leu His 85 90 95 Asp Gln Leu Gly Leu Arg Gln Gly Asp CysVal Ala Leu Phe Met Gly 100 105 110 Asn Glu Pro Ala Tyr Val Trp Ile TrpLeu Gly Leu Leu Lys Leu Gly 115 120 125 Cys Pro Met Ala Cys Leu Asn TyrAsn Ile Arg Ala Lys Ser Leu Leu 130 135 140 His Cys Phe Gln Cys Cys GlyAla Lys Val Leu Leu Ala Ser Pro Asp 145 150 155 160 Leu Gln Glu Ala ValGlu Glu Val Leu Pro Thr Leu Lys Lys Asp Ala 165 170 175 Val Ser Val PheTyr Val Ser Arg Thr Ser Asn Thr Asn Gly Val Asp 180 185 190 Thr Ile LeuAsp Lys Val Asp Gly Val Ser Ala Glu Pro Thr Pro Glu 195 200 205 Ser TrpArg Ser Glu Val Thr Phe Thr Thr Pro Ala Val Tyr Ile Tyr 210 215 220 ThrSer Gly Thr Thr Gly Leu Pro Lys Ala Ala Thr Ile Asn His His 225 230 235240 Arg Leu Arg Tyr Gly Thr Gly Leu Ala Met Ser Ser Gly Ile Thr Ala 245250 255 Gln Asp Val Ile Tyr Thr Thr Met Pro Leu Tyr His Ser Ala Ala Leu260 265 270 Met Ile Gly Leu His Gly Cys Ile Val Val Gly Ala Xaa Xaa XaaLeu 275 280 285 Cys Asp Lys Phe Ser Ala Ser Gln Phe Trp Asp Asp Cys ArgLys Tyr 290 295 300 Asn Val Thr Val Ile Gln Tyr Ile Gly Glu Leu Leu ArgTyr Leu Cys 305 310 315 320 Asn Thr Pro Gln Lys Pro Asn Asp Arg Asp HisLys Val Lys Lys Ala 325 330 335 Leu Gly Asn Gly Leu Arg Gly Asp Val TrpArg Glu Phe Ile Lys Arg 340 345 350 Phe Gly Asp Ile His Val Tyr Glu PheTyr Ala Ser Thr Glu Gly Asn 355 360 365 Ile Gly Phe Val Asn Tyr Pro ArgLys Ile Gly Ala Val Gly Arg Ala 370 375 380 Asn Tyr Leu Gln Arg Lys ValAla Arg Tyr Glu Leu Ile Lys Tyr Asp 385 390 395 400 Val Glu Lys Asp GluPro Val Arg Asp Ala Asn Gly Tyr Cys Ile Lys 405 410 415 Val Pro Lys GlyGlu Val Gly Leu Leu Val Cys Lys Ile Thr Gln Leu 420 425 430 Thr Pro PheIle Gly Tyr Ala Gly Gly Lys Thr Gln Thr Glu Lys Lys 435 440 445 Lys LeuArg Asp Val Phe Lys Lys Gly Asp Ile Tyr Phe Asn Ser Gly 450 455 460 AspLeu Leu Met Ile Asp Arg Glu Asn Phe Val Tyr Phe His Asp Arg 465 470 475480 Val Gly Asp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr Thr Glu 485490 495 Val Ala Asp Ile Val Gly Leu Val Asp Phe Val Glu Glu Val Asn Val500 505 510 Tyr Gly Val Pro Val Pro Gly His Glu Gly Arg Ile Gly Met AlaSer 515 520 525 Leu Lys Ile Lys Glu Asn Tyr Glu Phe Asn Gly Lys Lys LeuPhe Gln 530 535 540 His Ile Ala Glu Tyr Leu Pro Ser Tyr Ala Arg Pro ArgPhe Leu Arg 545 550 555 560 Ile Gln Asp Thr Ile Glu Ile Thr Gly Thr PheLys His Arg Lys Val 565 570 575 Thr Leu Met Glu Glu Gly Phe Asn Pro ThrVal Ile Lys Asp Thr Leu 580 585 590 Tyr Phe Met Asp Asp Ala Glu Lys ThrPhe Val Pro Met Thr Glu Asn 595 600 605 Ile Tyr Asn Ala Ile Ile Asp LysThr Leu Lys Leu 610 615 620 94 613 PRT Mus musculus 94 Ala Ala Asp ProGlu Ser Ser Glu Ser Gly Cys Ser Leu Ala Trp Arg 1 5 10 15 Leu Ala TyrLeu Ala Arg Glu Gln Pro Thr His Thr Phe Leu Ile His 20 25 30 Gly Ala GlnArg Phe Ser Tyr Ala Glu Ala Glu Arg Glu Ser Asn Arg 35 40 45 Ile Ala ArgAla Phe Leu Arg Ala Arg Gly Trp Thr Gly Gly Arg Arg 50 55 60 Gly Ser GlyArg Gly Ser Thr Glu Glu Gly Ala Arg Val Ala Pro Pro 65 70 75 80 Ala GlyAsp Ala Ala Ala Arg Gly Thr Thr Ala Pro Pro Leu Ala Pro 85 90 95 Gly AlaThr Val Ala Leu Leu Leu Pro Ala Gly Pro Asp Phe Leu Trp 100 105 110 IleTrp Phe Gly Leu Ala Lys Ala Gly Leu Arg Thr Ala Phe Val Pro 115 120 125Thr Ala Leu Arg Arg Gly Pro Leu Leu His Cys Leu Arg Ser Cys Gly 130 135140 Ala Ser Ala Leu Val Leu Ala Thr Glu Phe Leu Glu Ser Leu Glu Pro 145150 155 160 Asp Leu Pro Ala Leu Arg Ala Met Gly Leu His Leu Trp Ala ThrGly 165 170 175 Pro Glu Thr Asn Val Ala Gly Ile Ser Asn Leu Leu Ser GluAla Ala 180 185 190 Asp Gln Val Asp Glu Pro Val Pro Gly Tyr Leu Ser AlaPro Gln Asn 195 200 205 Ile Met Asp Thr Cys Leu Tyr Ile Phe Thr Ser GlyThr Thr Gly Leu 210 215 220 Pro Lys Ala Ala Arg Ile Ser His Leu Lys ValLeu Gln Cys Gln Gly 225 230 235 240 Phe Tyr His Leu Cys Gly Val His GlnGlu Asp Val Ile Tyr Leu Ala 245 250 255 Leu Pro Leu Tyr His Met Ser GlySer Leu Leu Gly Ile Val Gly Cys 260 265 270 Leu Gly Ile Gly Ala Thr ValVal Leu Lys Pro Lys Phe Ser Ala Ser 275 280 285 Gln Phe Trp Asp Asp CysGln Lys His Arg Val Thr Val Phe Gln Tyr 290 295 300 Ile Gly Glu Leu CysArg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala 305 310 315 320 Glu Phe AspHis Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro 325 330 335 Asp ThrTrp Glu Arg Phe Leu Arg Arg Phe Gly Pro Leu Gln Ile Leu 340 345 350 GluThr Tyr Gly Met Thr Glu Gly Asn Val Ala Thr Phe Asn Tyr Thr 355 360 365Gly Arg Gln Gly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile 370 375380 Phe Pro Phe Ser Leu Ile Arg Tyr Asp Val Met Thr Gly Glu Pro Ile 385390 395 400 Arg Asn Ala Gln Gly His Cys Met Thr Thr Ser Pro Gly Glu ProGly 405 410 415 Leu Leu Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu GlyTyr Ala 420 425 430 Gly Ala Pro Glu Leu Ala Lys Asp Lys Leu Leu Lys AspVal Phe Trp 435 440 445 Ser Gly Asp Val Phe Phe Asn Thr Gly Asp Leu LeuVal Cys Asp Glu 450 455 460 Gln Gly Phe Leu His Phe His Asp Arg Thr GlyAsp Thr Ile Arg Trp 465 470 475 480 Lys Gly Glu Asn Val Ala Thr Thr GluVal Ala Glu Val Leu Glu Thr 485 490 495 Leu Asp Phe Leu Gln Glu Val AsnIle Tyr Gly Val Thr Val Pro Gly 500 505 510 His Glu Gly Arg Ala Gly MetAla Ala Leu Ala Leu Arg Pro Pro Gln 515 520 525 Ala Leu Asn Leu Val GlnLeu Tyr Ser His Val Ser Glu Asn Leu Pro 530 535 540 Pro Tyr Ala Arg ProArg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr 545 550 555 560 Thr Glu ThrPhe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe 565 570 575 Asp ProSer Val Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Asp Ile 580 585 590 GlyAla Tyr Leu Pro Leu Thr Pro Ala Arg Tyr Ser Ala Leu Leu Ser 595 600 605Gly Asp Leu Arg Ile 610 95 506 PRT Mus musculus 95 His Ala Ser Ala HisAla Ser Gly Met Ala Lys Leu Gly Val Glu Ala 1 5 10 15 Ala Leu Ile AsnThr Asn Leu Arg Arg Asp Ala Leu Arg His Cys Leu 20 25 30 Asp Thr Ser LysAla Arg Ala Leu Ile Phe Gly Ser Glu Met Ala Ser 35 40 45 Ala Ile Cys GluIle His Ala Ser Leu Glu Pro Thr Leu Ser Leu Phe 50 55 60 Cys Ser Gly SerTrp Glu Pro Ser Thr Val Pro Val Ser Thr Glu His 65 70 75 80 Leu Asp ProLeu Leu Glu Asp Ala Pro Lys His Leu Pro Ser His Pro 85 90 95 Asp Lys GlyPhe Thr Asp Lys Leu Phe Tyr Ile Tyr Thr Ser Gly Thr 100 105 110 Thr GlyLeu Pro Lys Ala Ala Ile Val Val His Ser Arg Tyr Tyr Arg 115 120 125 MetAla Ser Leu Val Tyr Tyr Gly Phe Arg Met Arg Pro Asp Asp Ile 130 135 140Val Tyr Asp Cys Leu Pro Leu Tyr His Ser Ser Arg Lys His Arg Gly 145 150155 160 Asp Trp Gln Cys Leu Leu His Gly Met Thr Val Val Ile Arg Lys Lys165 170 175 Phe Ser Ala Ser Arg Phe Trp Asp Asp Cys Ile Lys Tyr Asn CysThr 180 185 190 Val Val Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu Leu AsnGln Pro 195 200 205 Pro Arg Glu Ala Glu Ser Arg His Lys Val Arg Met AlaLeu Gly Asn 210 215 220 Gly Leu Arg Gln Ser Ile Trp Thr Asp Phe Ser SerArg Phe His Ile 225 230 235 240 Pro Gln Val Ala Glu Phe Tyr Gly Ala ThrGlu Cys Asn Cys Ser Leu 245 250 255 Gly Asn Phe Asp Ser Arg Val Gly AlaCys Gly Phe Asn Ser Arg Ile 260 265 270 Leu Ser Phe Val Tyr Pro Ile ArgLeu Val Arg Val Asn Glu Asp Thr 275 280 285 Met Glu Leu Ile Arg Gly ProAsp Gly Val Cys Ile Pro Cys Gln Pro 290 295 300 Gly Gln Pro Gly Gln LeuVal Gly Arg Ile Ile Gln Gln Asp Pro Leu 305 310 315 320 Arg Arg Phe AspGly Tyr Leu Asn Gln Gly Ala Asn Asn Lys Lys Ile 325 330 335 Ala Asn AspVal Phe Lys Lys Gly Asp Gln Ala Tyr Leu Thr Gly Asp 340 345 350 Val LeuVal Met Asp Glu Leu Gly Tyr Leu Tyr Phe Arg Asp Arg Thr 355 360 365 GlyAsp Thr Phe Arg Trp Lys Gly Glu Asn Val Ser Thr Thr Glu Val 370 375 380Glu Gly Thr Leu Ser Arg Leu Leu His Met Ala Asp Val Ala Val Tyr 385 390395 400 Gly Val Glu Val Pro Gly Thr Glu Gly Arg Ala Gly Met Ala Ala Val405 410 415 Ala Ser Pro Ile Ser Asn Cys Asp Leu Glu Ser Phe Ala Gln ThrLeu 420 425 430 Lys Lys Glu Leu Pro Leu Tyr Ala Arg Pro Ile Phe Leu ArgPhe Leu 435 440 445 Pro Glu Leu His Lys Thr Gly Thr Phe Lys Phe Gln LysThr Glu Leu 450 455 460 Arg Lys Glu Gly Phe Asp Pro Ser Val Val Lys AspPro Leu Phe Tyr 465 470 475 480 Leu Asp Ala Arg Lys Gly Cys Tyr Val AlaLeu Asp Gln Glu Ala Tyr 485 490 495 Thr Arg Ile Gln Ala Gly Glu Glu LysLeu 500 505 96 662 PRT Mus musculus 96 Met Ala Leu Ala Leu Arg Trp PheLeu Gly Asp Pro Thr Cys Leu Val 1 5 10 15 Leu Leu Gly Leu Ala Leu LeuGly Arg Pro Trp Ile Ser Ser Trp Met 20 25 30 Pro His Trp Leu Ser Leu ValGly Ala Ala Leu Thr Leu Phe Leu Leu 35 40 45 Pro Leu Gln Pro Pro Pro GlyLeu Arg Trp Leu His Lys Asp Val Ala 50 55 60 Phe Thr Phe Lys Met Leu PheTyr Gly Leu Lys Phe Arg Arg Arg Leu 65 70 75 80 Asn Lys His Pro Pro GluThr Phe Val Asp Ala Leu Glu Arg Gln Ala 85 90 95 Leu Ala Trp Pro Asp ArgVal Ala Leu Val Cys Thr Gly Ser Glu Gly 100 105 110 Ser Ser Ile Thr AsnSer Gln Leu Asp Ala Arg Ser Cys Gln Ala Ala 115 120 125 Trp Val Leu LysAla Lys Leu Lys Asp Ala Val Ile Gln Asn Thr Arg 130 135 140 Asp Ala AlaAla Ile Leu Val Leu Pro Ser Lys Thr Ile Ser Ala Leu 145 150 155 160 SerVal Phe Leu Gly Leu Ala Lys Leu Gly Cys Pro Val Ala Trp Ile 165 170 175Asn Pro His Ser Arg Gly Met Pro Leu Leu His Ser Val Arg Ser Ser 180 185190 Gly Ala Ser Val Leu Ile Val Asp Pro Asp Leu Gln Glu Asn Leu Glu 195200 205 Glu Val Leu Pro Lys Leu Leu Ala Glu Asn Ile His Cys Phe Tyr Leu210 215 220 Gly His Ser Ser Pro Thr Pro Gly Val Glu Ala Leu Gly Ala SerLeu 225 230 235 240 Asp Ala Ala Pro Ser Asp Pro Val Pro Ala Ser Leu ArgAla Thr Ile 245 250 255 Lys Trp Lys Ser Pro Ala Ile Phe Ile Phe Thr SerGly Thr Thr Gly 260 265 270 Leu Pro Lys Pro Ala Ile Leu Ser His Glu ArgVal Ile Gln Val Ser 275 280 285 Asn Val Leu Ser Phe Cys Gly Cys Arg AlaAsp Asp Val Val Tyr Asp 290 295 300 Val Leu Pro Leu Tyr His Thr Ile GlyLeu Val Leu Gly Phe Leu Gly 305 310 315 320 Cys Leu Gln Val Gly Ala ThrCys Val Leu Ala Pro Lys Phe Ser Ala 325 330 335 Ser Arg Phe Trp Ala GluCys Arg Gln His Gly Val Thr Val Ile Leu 340 345 350 Tyr Val Gly Glu IleLeu Arg Tyr Leu Cys Asn Val Pro Glu Gln Pro 355 360 365 Glu Asp Lys IleHis Thr Val Arg Leu Ala Met Gly Thr Gly Leu Arg 370 375 380 Ala Asn ValTrp Lys Asn Phe Gln Gln Arg Phe Gly Pro Ile Arg Ile 385 390 395 400 TrpGlu Phe Tyr Gly Ser Thr Glu Gly Asn Val Gly Leu Met Asn Tyr 405 410 415Val Gly His Cys Gly Ala Val Gly Arg Thr Ser Cys Ile Leu Arg Met 420 425430 Leu Thr Pro Phe Glu Leu Val Gln Phe Asp Ile Glu Thr Ala Glu Pro 435440 445 Leu Arg Asp Lys Gln Gly Phe Cys Ile Pro Val Glu Pro Gly Lys Pro450 455 460 Gly Leu Leu Leu Thr Lys Val Arg Lys Asn Gln Pro Phe Leu GlyTyr 465 470 475 480 Arg Gly Ser Gln Ala Glu Ser Asn Arg Lys Leu Val AlaAsn Val Arg 485 490 495 Arg Val Gly Asp Leu Tyr Phe Asn Thr Gly Asp ValLeu Thr Leu Asp 500 505 510 Gln Glu Gly Phe Phe Tyr Phe Gln Asp Arg LeuGly Asp Thr Phe Arg 515 520 525 Trp Lys Gly Glu Asn Val Ser Thr Gly GluVal Glu Cys Val Leu Ser 530 535 540 Ser Leu Asp Phe Leu Glu Glu Val AsnVal Tyr Gly Val Pro Val Pro 545 550 555 560 Gly Cys Glu Gly Lys Val GlyMet Ala Ala Val Lys Leu Ala Pro Gly 565 570 575 Lys Thr Phe Asp Gly GlnLys Leu Tyr Gln His Val Arg Ser Trp Leu 580 585 590 Pro Ala Tyr Ala ThrPro His Phe Ile Arg Ile Gln Asp Ser Leu Glu 595 600 605 Ile Thr Asn ThrTyr Lys Leu Val Lys Ser Arg Leu Val Arg Glu Gly 610 615 620 Phe Asp ValGly Ile Ile Ala Asp Pro Leu Tyr Ile Leu Asp Asn Lys 625 630 635 640 AlaGln Thr Phe Arg Ser Leu Met Pro Asp Val Tyr Gln Ala Val Cys 645 650 655Glu Gly Thr Trp Asn Leu 660 97 650 PRT Caenorhabditis elegans 97 Met LysLeu Glu Glu Leu Val Thr Val Met Leu Leu Thr Val Ala Val 1 5 10 15 IleAla Gln Asn Leu Pro Ile Gly Val Ile Leu Ala Gly Val Leu Ile 20 25 30 LeuTyr Ile Thr Val Val His Gly Asp Phe Ile Tyr Arg Ser Tyr Leu 35 40 45 ThrLeu Asn Arg Asp Leu Thr Gly Leu Ala Leu Ile Ile Glu Val Lys 50 55 60 IleAsp Leu Trp Trp Arg Leu His Gln Asn Lys Gly Ile His Glu Leu 65 70 75 80Phe Leu Asp Ile Val Lys Lys Asn Pro Asn Lys Pro Ala Met Ile Asp 85 90 95Ile Glu Thr Asn Thr Thr Glu Thr Tyr Ala Glu Phe Asn Ala His Cys 100 105110 Asn Arg Tyr Ala Asn Tyr Phe Gln Gly Leu Gly Tyr Arg Ser Gly Asp 115120 125 Val Val Ala Leu Tyr Met Glu Asn Ser Val Glu Phe Val Ala Ala Trp130 135 140 Met Gly Leu Ala Lys Ile Gly Val Val Thr Ala Trp Ile Asn SerAsn 145 150 155 160 Leu Lys Arg Glu Gln Leu Val His Cys Ile Thr Ala SerLys Thr Lys 165 170 175 Ala Ile Ile Thr Ser Val Thr Leu Gln Asn Ile MetLeu Asp Ala Ile 180 185 190 Asp Gln Lys Leu Phe Asp Val Glu Gly Ile GluVal Tyr Ser Val Gly 195 200 205 Glu Pro Lys Lys Asn Ser Gly Phe Lys AsnLeu Lys Lys Lys Leu Asp 210 215 220 Ala Gln Ile Thr Thr Glu Pro Lys ThrLeu Asp Ile Val Asp Phe Lys 225 230 235 240 Ser Ile Leu Cys Phe Ile TyrThr Ser Gly Thr Thr Gly Met Pro Lys 245 250 255 Ala Ala Val Met Lys HisPhe Arg Tyr Tyr Ser Ile Ala Val Gly Ala 260 265 270 Ala Lys Ser Phe GlyIle Arg Pro Ser Asp Arg Met Tyr Val Ser Met 275 280 285 Pro Ile Tyr HisThr Ala Ala Gly Ile Leu Gly Val Gly Gln Ala Leu 290 295 300 Leu Gly GlySer Ser Cys Val Ile Arg Lys Lys Phe Ser Ala Ser Asn 305 310 315 320 PheTrp Arg Asp Cys Val Lys Tyr Asp Cys Thr Val Ser Gln Tyr Ile 325 330 335Gly Glu Ile Cys Arg Tyr Leu Leu Ala Gln Pro Val Val Glu Glu Glu 340 345350 Ser Arg His Arg Met Arg Leu Leu Val Gly Asn Gly Leu Arg Ala Glu 355360 365 Ile Trp Gln Pro Phe Val Asp Arg Phe Arg Val Arg Ile Gly Glu Leu370 375 380 Tyr Gly Ser Thr Glu Gly Thr Ser Ser Leu Val Asn Ile Asp GlyHis 385 390 395 400 Val Gly Ala Cys Gly Phe Leu Pro Ile Ser Pro Leu ThrLys Lys Met 405 410 415 His Pro Val Arg Leu Ile Lys Val Asp Asp Val ThrGly Glu Ala Ile 420 425 430 Arg Thr Ser Asp Gly Leu Cys Ile Ala Cys AsnPro Gly Glu Ser Gly 435 440 445 Ala Met Val Ser Thr Ile Arg Lys Asn AsnPro Leu Leu Gln Phe Glu 450 455 460 Gly Tyr Leu Asn Lys Lys Glu Thr AsnLys Lys Ile Ile Arg Asp Val 465 470 475 480 Phe Ala Lys Gly Asp Ser CysPhe Leu Thr Gly Asp Leu Leu His Trp 485 490 495 Asp Arg Leu Gly Tyr ValTyr Phe Lys Asp Arg Thr Gly Asp Thr Phe 500 505 510 Arg Trp Lys Gly GluAsn Val Ser Thr Thr Glu Val Glu Ala Ile Leu 515 520 525 His Pro Ile ThrGly Leu Ser Asp Ala Thr Val Tyr Gly Val Glu Val 530 535 540 Pro Gln ArgGlu Gly Arg Val Gly Met Ala Ser Val Val Arg Val Val 545 550 555 560 SerHis Glu Glu Asp Glu Thr Gln Phe Val His Arg Val Gly Ala Arg 565 570 575Leu Ala Ser Ser Leu Thr Ser Tyr Ala Ile Pro Gln Phe Met Arg Ile 580 585590 Cys Gln Asp Val Glu Lys Thr Gly Thr Phe Lys Leu Val Lys Thr Asn 595600 605 Leu Gln Arg Leu Gly Ile Met Asp Ala Pro Ser Asp Ser Ile Tyr Ile610 615 620 Tyr Asn Ser Glu Asn Arg Asn Phe Val Pro Phe Asp Asn Asp LeuArg 625 630 635 640 Cys Lys Val Ser Leu Gly Ser Tyr Pro Phe 645 650 98623 PRT Saccharomyces cerevisiae 98 Met Ser Pro Ile Gln Val Val Val PheAla Leu Ser Arg Ile Phe Leu 1 5 10 15 Leu Leu Phe Arg Leu Ile Lys LeuIle Ile Thr Pro Ile Gln Lys Ser 20 25 30 Leu Gly Tyr Leu Phe Gly Asn TyrPhe Asp Glu Leu Asp Arg Lys Tyr 35 40 45 Arg Tyr Lys Glu Asp Trp Tyr IleIle Pro Tyr Phe Leu Lys Ser Val 50 55 60 Phe Cys Tyr Ile Ile Asp Val ArgArg His Arg Phe Gln Asn Trp Tyr 65 70 75 80 Leu Phe Ile Lys Gln Val GlnGln Asn Gly Asp His Leu Ala Ile Ser 85 90 95 Tyr Thr Arg Pro Met Ala GluLys Gly Glu Phe Gln Leu Glu Thr Phe 100 105 110 Thr Tyr Ile Glu Thr TyrAsn Ile Val Leu Arg Leu Ser His Ile Leu 115 120 125 His Phe Asp Tyr AsnVal Gln Ala Gly Asp Tyr Val Ala Ile Asp Cys 130 135 140 Thr Asn Lys ProLeu Phe Val Phe Leu Trp Leu Ser Leu Trp Asn Ile 145 150 155 160 Gly AlaIle Pro Ala Phe Leu Asn Tyr Asn Thr Lys Gly Thr Pro Leu 165 170 175 ValHis Ser Leu Lys Ile Ser Asn Ile Thr Gln Val Phe Ile Asp Pro 180 185 190Asp Ala Ser Asn Pro Ile Arg Glu Ser Glu Glu Glu Ile Lys Asn Ala 195 200205 Leu Pro Asp Val Lys Leu Asn Tyr Leu Glu Glu Gln Asp Leu Met His 210215 220 Glu Leu Leu Asn Ser Gln Ser Pro Glu Phe Leu Gln Gln Asp Asn Val225 230 235 240 Arg Thr Pro Leu Gly Leu Thr Asp Phe Lys Pro Ser Met LeuIle Tyr 245 250 255 Thr Ser Gly Thr Thr Gly Leu Pro Lys Ser Ala Ile MetSer Trp Arg 260 265 270 Lys Ser Ser Val Gly Cys Gln Val Phe Gly His ValLeu His Met Thr 275 280 285 Asn Glu Ser Thr Val Phe Thr Ala Met Pro LeuPhe His Ser Thr Ala 290 295 300 Ala Leu Leu Gly Ala Cys Ala Ile Leu SerHis Gly Gly Cys Leu Ala 305 310 315 320 Leu Ser His Lys Phe Ser Ala SerThr Phe Trp Lys Gln Val Tyr Leu 325 330 335 Thr Gly Ala Thr His Ile GlnTyr Val Gly Glu Val Cys Arg Tyr Leu 340 345 350 Leu His Thr Pro Ile SerLys Tyr Glu Lys Met His Lys Val Lys Val 355 360 365 Ala Tyr Gly Asn GlyLeu Arg Pro Asp Ile Trp Gln Asp Phe Arg Lys 370 375 380 Arg Phe Asn IleGlu Val Ile Gly Glu Phe Tyr Ala Ala Thr Glu Ala 385 390 395 400 Pro PheAla Thr Thr Thr Phe Gln Lys Gly Asp Phe Gly Ile Gly Ala 405 410 415 CysArg Asn Tyr Gly Thr Ile Ile Gln Trp Phe Leu Ser Phe Gln Gln 420 425 430Thr Leu Val Arg Met Asp Pro Asn Asp Asp Ser Val Ile Tyr Arg Asn 435 440445 Ser Lys Gly Phe Cys Glu Val Ala Pro Val Gly Glu Pro Gly Glu Met 450455 460 Leu Met Arg Ile Phe Phe Pro Lys Lys Pro Glu Thr Ser Phe Gln Gly465 470 475 480 Tyr Leu Gly Asn Ala Lys Glu Thr Lys Ser Lys Val Val ArgAsp Val 485 490 495 Phe Arg Arg Gly Asp Ala Trp Tyr Arg Cys Gly Asp LeuLeu Lys Ala 500 505 510 Asp Glu Tyr Gly Leu Trp Tyr Phe Leu Asp Arg MetGly Asp Thr Phe 515 520 525 Arg Trp Lys Ser Glu Asn Val Ser Thr Thr GluVal Glu Asp Gln Leu 530 535 540 Thr Ala Ser Asn Lys Glu Gln Tyr Ala GlnVal Leu Val Val Gly Ile 545 550 555 560 Lys Val Pro Lys Tyr Glu Gly ArgAla Gly Phe Ala Val Ile Lys Leu 565 570 575 Thr Asp Asn Ser Leu Asp IleThr Ala Lys Thr Lys Leu Leu Asn Asp 580 585 590 Ser Leu Ser Arg Leu AsnLeu Pro Ser Tyr Ala Met Pro Leu Phe Val 595 600 605 Lys Phe Val Asp GluIle Lys Met Thr Asp Asn Leu Ile Lys Phe 610 615 620 99 597 PRTMycobacterium tuberculosis 99 Met Ser Asp Tyr Tyr Gly Gly Ala His ThrThr Val Arg Leu Ile Asp 1 5 10 15 Leu Ala Thr Arg Met Pro Arg Val LeuAla Asp Thr Pro Val Ile Val 20 25 30 Arg Gly Ala Met Thr Gly Leu Leu AlaArg Pro Asn Ser Lys Ala Ser 35 40 45 Ile Gly Thr Val Phe Gln Asp Arg AlaAla Arg Tyr Gly Asp Arg Val 50 55 60 Phe Leu Lys Phe Gly Asp Gln Gln LeuThr Tyr Arg Asp Ala Asn Ala 65 70 75 80 Thr Ala Asn Arg Tyr Ala Ala ValLeu Ala Ala Arg Gly Val Gly Pro 85 90 95 Gly Asp Val Val Gly Ile Met LeuArg Asn Ser Pro Ser Thr Val Leu 100 105 110 Ala Met Leu Ala Thr Val LysCys Gly Ala Ile Ala Gly Met Leu Asn 115 120 125 Tyr His Gln Arg Gly GluVal Leu Ala His Ser Leu Gly Leu Leu Asp 130 135 140 Ala Lys Val Leu IleAla Glu Ser Asp Leu Val Ser Ala Val Ala Glu 145 150 155 160 Cys Gly AlaSer Arg Gly Arg Val Ala Gly Asp Val Leu Thr Val Glu 165 170 175 Asp ValGlu Arg Phe Ala Thr Thr Ala Pro Ala Thr Asn Pro Ala Ser 180 185 190 AlaSer Ala Val Gln Ala Lys Asp Thr Ala Phe Tyr Ile Phe Thr Ser 195 200 205Gly Thr Thr Gly Phe Pro Lys Ala Ser Val Met Thr His His Arg Trp 210 215220 Leu Arg Ala Leu Ala Val Phe Gly Gly Met Gly Leu Arg Leu Lys Gly 225230 235 240 Ser Asp Thr Leu Tyr Ser Cys Leu Pro Leu Tyr His Asn Asn AlaLeu 245 250 255 Thr Val Ala Val Ser Ser Val Ile Asn Ser Gly Ala Thr LeuAla Leu 260 265 270 Gly Lys Ser Phe Ser Ala Ser Arg Phe Trp Asp Glu ValIle Ala Asn 275 280 285 Arg Ala Thr Ala Phe Val Tyr Ile Gly Glu Ile CysArg Tyr Leu Leu 290 295 300 Asn Gln Pro Ala Lys Pro Thr Asp Arg Ala HisGln Val Arg Val Ile 305 310 315 320 Cys Gly Asn Gly Leu Arg Pro Glu IleTrp Asp Glu Phe Thr Thr Arg 325 330 335 Phe Gly Val Ala Arg Val Cys GluPhe Tyr Ala Ala Ser Glu Gly Asn 340 345 350 Ser Ala Phe Ile Asn Ile PheAsn Val Pro Arg Thr Ala Gly Val Ser 355 360 365 Pro Met Pro Leu Ala PheVal Glu Tyr Asp Leu Asp Thr Gly Asp Pro 370 375 380 Leu Arg Asp Ala SerGly Arg Val Arg Arg Val Pro Asp Gly Glu Pro 385 390 395 400 Gly Leu LeuLeu Ser Arg Val Asn Arg Leu Gln Pro Phe Asp Gly Tyr 405 410 415 Thr AspPro Val Ala Ser Glu Lys Lys Leu Val Arg Asn Ala Phe Arg 420 425 430 AspGly Asp Cys Trp Phe Asn Thr Gly Asp Val Met Ser Pro Gln Gly 435 440 445Met Gly His Ala Ala Phe Val Asp Arg Leu Gly Asp Thr Phe Arg Trp 450 455460 Lys Gly Glu Asn Val Ala Thr Thr Gln Val Glu Ala Ala Leu Ala Ser 465470 475 480 Asp Gln Thr Val Glu Glu Cys Thr Val Tyr Gly Val Gln Ile ProArg 485 490 495 Thr Gly Gly Arg Ala Gly Met Ala Ala Ile Thr Leu Arg AlaGly Ala 500 505 510 Glu Phe Asp Gly Gln Ala Leu Ala Arg Thr Val Tyr GlyHis Leu Pro 515 520 525 Gly Tyr Ala Leu Pro Leu Phe Val Arg Val Val GlySer Leu Ala His 530 535 540 Thr Thr Thr Phe Lys Ser Arg Lys Val Glu LeuArg Asn Gln Ala Tyr 545 550 555 560 Gly Ala Asp Ile Glu Asp Pro Leu TyrVal Leu Ala Gly Pro Asp Glu 565 570 575 Gly Tyr Val Pro Tyr Tyr Ala GluTyr Pro Glu Glu Val Ser Leu Gly 580 585 590 Arg Arg Pro Gln Gly 595 100304 PRT concensus FATP signature sequence 100 Tyr Ile Tyr Thr Ser GlyThr Thr Gly Leu Pro Lys Ala Ala Ile Ile 1 5 10 15 Val His Ser Arg TyrTyr Arg Gly Ala Ala Leu His Ser Gly Arg Met 20 25 30 Arg Pro Asp Val ValTyr Asp Cys Leu Pro Leu Tyr His Ser Ala Ala 35 40 45 Leu Ile Leu Gly IleGly Gln Cys Leu Leu His Gly Ala Thr Val Val 50 55 60 Leu Arg Lys Lys PheSer Ala Ser Arg Phe Trp Asp Asp Cys Val Lys 65 70 75 80 Tyr Asn Val ThrVal Ile Gln Tyr Ile Gly Glu Leu Cys Arg Tyr Leu 85 90 95 Leu Asn Gln ProPro Arg Pro Ala Glu Arg Arg His Lys Val Arg Leu 100 105 110 Ala Val GlyAsn Gly Leu Arg Pro Asp Ile Trp Glu Glu Phe Val Ser 115 120 125 Arg PheGly Ile Pro Gln Ile Gly Glu Phe Tyr Gly Ala Thr Glu Gly 130 135 140 AsnCys Ser Leu Met Asn Tyr Asp Gly Lys Val Gly Ala Cys Gly Ser 145 150 155160 Arg Ile Leu Lys Lys Val Tyr Pro Ile Arg Leu Val Lys Val Asp Glu 165170 175 Asp Thr Gly Glu Pro Ile Arg Asp Ala Gln Gly Leu Cys Ile Pro Cys180 185 190 Gln Pro Gly Glu Pro Gly Leu Leu Val Gly Arg Ile Asn Gln GlnAsp 195 200 205 Pro Phe Arg Gly Phe Gly Tyr Gly Ser Glu Gly Ala Thr AsnLys Lys 210 215 220 Ile Ala Arg Asp Val Phe Lys Lys Gly Asp Val Ala PheAsn Thr Gly 225 230 235 240 Asp Val Leu Val Met Asp Glu Leu Gly Tyr LeuTyr Phe Arg Asp Arg 245 250 255 Thr Gly Asp Thr Phe Arg Trp Lys Gly GluAsn Val Ser Thr Thr Glu 260 265 270 Val Glu Gly Val Leu Ser Arg Leu AspPhe Val Ala Glu Val Asn Val 275 280 285 Tyr Gly Val Thr Val Pro Gly HisGlu Gly Arg Ala Gly Met Ala Ala 290 295 300 101 2166 DNA Homo sapiensCDS (19)...(2124) 101 cgacccacgc gtccgggg atg ttt gcg agc ggc tgg aaccag acg gtg ccg 51 Met Phe Ala Ser Gly Trp Asn Gln Thr Val Pro 1 5 10ata gag gaa gcg ggc tcc atg gct gcc ctc ctg ctg ctg ccc ctg ctg 99 IleGlu Glu Ala Gly Ser Met Ala Ala Leu Leu Leu Leu Pro Leu Leu 15 20 25 ctgttg cta ccg ctg ctg ctg ctg ctg aag cta cac ctc tgg ccg cag 147 Leu LeuLeu Pro Leu Leu Leu Leu Leu Lys Leu His Leu Trp Pro Gln 30 35 40 ttg cgctgg ctt ccg gcg gac ttg gcc ttt gcg gtg cga gct ctg tgc 195 Leu Arg TrpLeu Pro Ala Asp Leu Ala Phe Ala Val Arg Ala Leu Cys 45 50 55 tgc aaa agggct ctt cga gct cgc gcc ctg gcc gcg gct gcc gcc gac 243 Cys Lys Arg AlaLeu Arg Ala Arg Ala Leu Ala Ala Ala Ala Ala Asp 60 65 70 75 ccg gaa ggtccc gag ggg ggc tgc agc ctg gcc tgg cgc ctc gcg gaa 291 Pro Glu Gly ProGlu Gly Gly Cys Ser Leu Ala Trp Arg Leu Ala Glu 80 85 90 ctg gcc cag cagcgc gcc gcg cac acc ttt ctc att cac ggc tcg cgg 339 Leu Ala Gln Gln ArgAla Ala His Thr Phe Leu Ile His Gly Ser Arg 95 100 105 cgc ttt agc tactca gag gcg gag cgc gag agt aac agg gct gca cgc 387 Arg Phe Ser Tyr SerGlu Ala Glu Arg Glu Ser Asn Arg Ala Ala Arg 110 115 120 gcc ttc cta cgtgcg cta ggc tgg gac tgg gga ccc gac ggc ggc gac 435 Ala Phe Leu Arg AlaLeu Gly Trp Asp Trp Gly Pro Asp Gly Gly Asp 125 130 135 agc ggc gag gggagc gct gga gaa ggc gag cgg gca gcg ccg gga gcc 483 Ser Gly Glu Gly SerAla Gly Glu Gly Glu Arg Ala Ala Pro Gly Ala 140 145 150 155 gga gat gcagcg gcc gga agc ggc gcg gag ttt gcc gga ggg gac ggt 531 Gly Asp Ala AlaAla Gly Ser Gly Ala Glu Phe Ala Gly Gly Asp Gly 160 165 170 gcc gcc agaggt gga gga gag ccc gcc gcc cct ctg tca cct gga gca 579 Ala Ala Arg GlyGly Gly Glu Pro Ala Ala Pro Leu Ser Pro Gly Ala 175 180 185 act gtg gcgctg ctc ctc ccc gct ggc cca gag ttt ctg tgg ctc tgg 627 Thr Val Ala LeuLeu Leu Pro Ala Gly Pro Glu Phe Leu Trp Leu Trp 190 195 200 ttc ggg ctggcc aag gcc ggc ctg cgc act gcc ttt gtg ccc acc gcc 675 Phe Gly Leu AlaLys Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala 205 210 215 ctg cgc cggggc ccc ctg ctg cac tgc ctc cgc agc tgc ggc gcg cgc 723 Leu Arg Arg GlyPro Leu Leu His Cys Leu Arg Ser Cys Gly Ala Arg 220 225 230 235 gcg ctggtg ctg gcg cca gag ttt ctg gag tcc ctg gag ccg gac ctg 771 Ala Leu ValLeu Ala Pro Glu Phe Leu Glu Ser Leu Glu Pro Asp Leu 240 245 250 ccc gccctg aga gcc atg ggg ctc cac ctg tgg gct gca ggc cca gga 819 Pro Ala LeuArg Ala Met Gly Leu His Leu Trp Ala Ala Gly Pro Gly 255 260 265 acc caccct gct gga att agc gat ttg ctg gct gaa gtg tcc gct gaa 867 Thr His ProAla Gly Ile Ser Asp Leu Leu Ala Glu Val Ser Ala Glu 270 275 280 gtg gatggg cca gtg cca gga tac ctc tct tcc ccc cag agc ata aca 915 Val Asp GlyPro Val Pro Gly Tyr Leu Ser Ser Pro Gln Ser Ile Thr 285 290 295 gac acgtgc ctg tac atc ttc acc tct ggc acc acg ggc ctc ccc aag 963 Asp Thr CysLeu Tyr Ile Phe Thr Ser Gly Thr Thr Gly Leu Pro Lys 300 305 310 315 gctgct cgg atc agt cat ctg aag atc ctg caa tgc cag ggc ttc tat 1011 Ala AlaArg Ile Ser His Leu Lys Ile Leu Gln Cys Gln Gly Phe Tyr 320 325 330 cagctg tgt ggt gtc cac cag gaa gat gtg atc tac ctc gcc ctc cca 1059 Gln LeuCys Gly Val His Gln Glu Asp Val Ile Tyr Leu Ala Leu Pro 335 340 345 ctctac cac atg tcc ggt tcc ctg ctg ggc atc gtg ggc tgc atg ggc 1107 Leu TyrHis Met Ser Gly Ser Leu Leu Gly Ile Val Gly Cys Met Gly 350 355 360 attggg gcc aca gtg gtg ctg aaa tcc aag ttc tcg gct ggt cag ttc 1155 Ile GlyAla Thr Val Val Leu Lys Ser Lys Phe Ser Ala Gly Gln Phe 365 370 375 tgggaa gat tgc cag cag cac agg gtg acg gtg ttc cag tac att ggg 1203 Trp GluAsp Cys Gln Gln His Arg Val Thr Val Phe Gln Tyr Ile Gly 380 385 390 395gag ctg tgc cga tac ctt gtc aac cag ccc ccg agc aag gca gaa cgt 1251 GluLeu Cys Arg Tyr Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg 400 405 410ggc cat aag gtc cgg ctg gca gtg ggc agc ggg ctg cgc cca gat acc 1299 GlyHis Lys Val Arg Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr 415 420 425tgg gag cgt ttt gtg cgg cgc ttc ggg ccc ctg cag gtg ctg gag aca 1347 TrpGlu Arg Phe Val Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr 430 435 440tat gga ctg aca gag ggc aac gtg gcc acc atc aac tac aca gga cag 1395 TyrGly Leu Thr Glu Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln 445 450 455cgg ggc gct gtg ggg cgt gct tcc tgg ctt tac aag cat atc ttc ccc 1443 ArgGly Ala Val Gly Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro 460 465 470475 ttc tcc ttg att cgc tat gat gtc acc aca gga gag cca att cgg gac 1491Phe Ser Leu Ile Arg Tyr Asp Val Thr Thr Gly Glu Pro Ile Arg Asp 480 485490 ccc cag ggg cac tgt atg gcc aca tct cca ggt gag cca ggg ctg ctg 1539Pro Gln Gly His Cys Met Ala Thr Ser Pro Gly Glu Pro Gly Leu Leu 495 500505 gtg gcc ccg gta agc cag cag tcc cca ttc ctg ggc tat gct ggc ggg 1587Val Ala Pro Val Ser Gln Gln Ser Pro Phe Leu Gly Tyr Ala Gly Gly 510 515520 cca gag ctg gcc cag ggg aag ttg cta aag gat gtc ttc cgg cct ggg 1635Pro Glu Leu Ala Gln Gly Lys Leu Leu Lys Asp Val Phe Arg Pro Gly 525 530535 gat gtt ttc ttc aac act ggg gac ctg ctg gtc tgc gat gac caa ggt 1683Asp Val Phe Phe Asn Thr Gly Asp Leu Leu Val Cys Asp Asp Gln Gly 540 545550 555 ttt ctc cgc ttc cat gat cgt act gga gac acc ttc agg tgg aag ggg1731 Phe Leu Arg Phe His Asp Arg Thr Gly Asp Thr Phe Arg Trp Lys Gly 560565 570 gag aat gtg gcc aca acc gag gtg gca gag gtc ttc gag gcc cta gat1779 Glu Asn Val Ala Thr Thr Glu Val Ala Glu Val Phe Glu Ala Leu Asp 575580 585 ttt ctt cag gag gtg aac gtc tat gga gtc act gtg cca ggg cat gaa1827 Phe Leu Gln Glu Val Asn Val Tyr Gly Val Thr Val Pro Gly His Glu 590595 600 ggc agg gct gga atg gca gcc cta gtt ctg cgt ccc ccc cac gct ttg1875 Gly Arg Ala Gly Met Ala Ala Leu Val Leu Arg Pro Pro His Ala Leu 605610 615 gac ctt atg cag ctc tac acc cac gtg tct gag aac ttg cca cct tat1923 Asp Leu Met Gln Leu Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr 620625 630 635 gcc cgg ccc cga ttc ctc agg ctc cag gag tct ttg gcc acc acagag 1971 Ala Arg Pro Arg Phe Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu640 645 650 acc ttc aaa cag cag aaa gtt cgg atg gca aat gag ggc ttc gacccc 2019 Thr Phe Lys Gln Gln Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro655 660 665 agc acc ctg tct gac cca ctg tac gtt ctg gac cag gct gta ggtgcc 2067 Ser Thr Leu Ser Asp Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala670 675 680 tac ctg ccc ctc aca act gcc cgg tac agc gcc ctc ctg gca ggaaac 2115 Tyr Leu Pro Leu Thr Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn685 690 695 ctt cga atc tgagaacttc cacacctgag gcacctgaga gaggaactct 2164Leu Arg Ile 700 gt 2166 102 702 PRT Homo sapiens 102 Met Phe Ala Ser GlyTrp Asn Gln Thr Val Pro Ile Glu Glu Ala Gly 1 5 10 15 Ser Met Ala AlaLeu Leu Leu Leu Pro Leu Leu Leu Leu Leu Pro Leu 20 25 30 Leu Leu Leu LeuLys Leu His Leu Trp Pro Gln Leu Arg Trp Leu Pro 35 40 45 Ala Asp Leu AlaPhe Ala Val Arg Ala Leu Cys Cys Lys Arg Ala Leu 50 55 60 Arg Ala Arg AlaLeu Ala Ala Ala Ala Ala Asp Pro Glu Gly Pro Glu 65 70 75 80 Gly Gly CysSer Leu Ala Trp Arg Leu Ala Glu Leu Ala Gln Gln Arg 85 90 95 Ala Ala HisThr Phe Leu Ile His Gly Ser Arg Arg Phe Ser Tyr Ser 100 105 110 Glu AlaGlu Arg Glu Ser Asn Arg Ala Ala Arg Ala Phe Leu Arg Ala 115 120 125 LeuGly Trp Asp Trp Gly Pro Asp Gly Gly Asp Ser Gly Glu Gly Ser 130 135 140Ala Gly Glu Gly Glu Arg Ala Ala Pro Gly Ala Gly Asp Ala Ala Ala 145 150155 160 Gly Ser Gly Ala Glu Phe Ala Gly Gly Asp Gly Ala Ala Arg Gly Gly165 170 175 Gly Glu Pro Ala Ala Pro Leu Ser Pro Gly Ala Thr Val Ala LeuLeu 180 185 190 Leu Pro Ala Gly Pro Glu Phe Leu Trp Leu Trp Phe Gly LeuAla Lys 195 200 205 Ala Gly Leu Arg Thr Ala Phe Val Pro Thr Ala Leu ArgArg Gly Pro 210 215 220 Leu Leu His Cys Leu Arg Ser Cys Gly Ala Arg AlaLeu Val Leu Ala 225 230 235 240 Pro Glu Phe Leu Glu Ser Leu Glu Pro AspLeu Pro Ala Leu Arg Ala 245 250 255 Met Gly Leu His Leu Trp Ala Ala GlyPro Gly Thr His Pro Ala Gly 260 265 270 Ile Ser Asp Leu Leu Ala Glu ValSer Ala Glu Val Asp Gly Pro Val 275 280 285 Pro Gly Tyr Leu Ser Ser ProGln Ser Ile Thr Asp Thr Cys Leu Tyr 290 295 300 Ile Phe Thr Ser Gly ThrThr Gly Leu Pro Lys Ala Ala Arg Ile Ser 305 310 315 320 His Leu Lys IleLeu Gln Cys Gln Gly Phe Tyr Gln Leu Cys Gly Val 325 330 335 His Gln GluAsp Val Ile Tyr Leu Ala Leu Pro Leu Tyr His Met Ser 340 345 350 Gly SerLeu Leu Gly Ile Val Gly Cys Met Gly Ile Gly Ala Thr Val 355 360 365 ValLeu Lys Ser Lys Phe Ser Ala Gly Gln Phe Trp Glu Asp Cys Gln 370 375 380Gln His Arg Val Thr Val Phe Gln Tyr Ile Gly Glu Leu Cys Arg Tyr 385 390395 400 Leu Val Asn Gln Pro Pro Ser Lys Ala Glu Arg Gly His Lys Val Arg405 410 415 Leu Ala Val Gly Ser Gly Leu Arg Pro Asp Thr Trp Glu Arg PheVal 420 425 430 Arg Arg Phe Gly Pro Leu Gln Val Leu Glu Thr Tyr Gly LeuThr Glu 435 440 445 Gly Asn Val Ala Thr Ile Asn Tyr Thr Gly Gln Arg GlyAla Val Gly 450 455 460 Arg Ala Ser Trp Leu Tyr Lys His Ile Phe Pro PheSer Leu Ile Arg 465 470 475 480 Tyr Asp Val Thr Thr Gly Glu Pro Ile ArgAsp Pro Gln Gly His Cys 485 490 495 Met Ala Thr Ser Pro Gly Glu Pro GlyLeu Leu Val Ala Pro Val Ser 500 505 510 Gln Gln Ser Pro Phe Leu Gly TyrAla Gly Gly Pro Glu Leu Ala Gln 515 520 525 Gly Lys Leu Leu Lys Asp ValPhe Arg Pro Gly Asp Val Phe Phe Asn 530 535 540 Thr Gly Asp Leu Leu ValCys Asp Asp Gln Gly Phe Leu Arg Phe His 545 550 555 560 Asp Arg Thr GlyAsp Thr Phe Arg Trp Lys Gly Glu Asn Val Ala Thr 565 570 575 Thr Glu ValAla Glu Val Phe Glu Ala Leu Asp Phe Leu Gln Glu Val 580 585 590 Asn ValTyr Gly Val Thr Val Pro Gly His Glu Gly Arg Ala Gly Met 595 600 605 AlaAla Leu Val Leu Arg Pro Pro His Ala Leu Asp Leu Met Gln Leu 610 615 620Tyr Thr His Val Ser Glu Asn Leu Pro Pro Tyr Ala Arg Pro Arg Phe 625 630635 640 Leu Arg Leu Gln Glu Ser Leu Ala Thr Thr Glu Thr Phe Lys Gln Gln645 650 655 Lys Val Arg Met Ala Asn Glu Gly Phe Asp Pro Ser Thr Leu SerAsp 660 665 670 Pro Leu Tyr Val Leu Asp Gln Ala Val Gly Ala Tyr Leu ProLeu Thr 675 680 685 Thr Ala Arg Tyr Ser Ala Leu Leu Ala Gly Asn Leu ArgIle 690 695 700 103 19 DNA Artificial Sequence Oligonucleotide 103cccccaccag agaggctcc 19 104 19 DNA Artificial Sequence Oligonucleotide104 ccacccccgg aaagcctgc 19 105 19 DNA Artificial SequenceOligonucleotide 105 ggagcctctc tggtggggg 19

What is claimed is:
 1. A method for identifying an agent which is aninhibitor of fatty acid uptake by a Fatty Acid Transport Protein (FATP),said FATP encoded by a polynucleotide comprising a nucleotide sequencewhich encodes a protein consisting of the amino acid sequence of SEQ IDNO:49, comprising the steps of: a) maintaining test cells expressingsaid polynucleotide in the presence of a fatty acid and an agent to betested as an inhibitor of fatty acid uptake; b) measuring uptake of thefatty acid in the test cells; and c) comparing uptake of the fatty acidin the test cells with uptake of the fatty acid in suitable controlcells; wherein lower uptake of the fatty acid in the test cells comparedto uptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 2. A methodfor identifying an agent which is an inhibitor of fatty acid uptake by aprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP2, wherein said polynucleotide hybridizes to a complement of apolynucleotide consisting of SEQ ID NO:48 under stringency conditions of6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at65° C., comprising the steps of: a) maintaining test cells expressingsaid polynucleotide in the presence of a fatty acid and an agent to betested as an inhibitor of fatty uptake; b) measuring uptake of the fattyacid in the test cells; and c) comparing uptake of the fatty acid in thetest cells with uptake of the fatty acid in suitable control cells;wherein lower uptake of the fatty acid in the test cells compared touptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 3. A methodfor identifying an agent which is an inhibitor of fatty acid uptake by aprotein, said protein having fatty acid transport activity and beingencoded by a nucleic acid encoding a fatty acid transport proteincomprising an amino acid sequence having at least 95% amino acidsequence identity with the amino acid sequence of SEQ ID NO:49,comprising the steps of: a) maintaining test cells expressing saidpolynucleotide in the presence of a fatty acid and an agent to be testedas an inhibitor of fatty acid uptake; b) measuring uptake of the fattyacid in the test calls; and c) comparing uptake of the fatty acid in thetest cells with uptake of the fatty acid in suitable control cells;wherein lower uptake of the fatty acid in the test cells compared touptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 4. A methodfor identifying an agent which is an inhibitor of a protein, saidprotein encoded by a polynucleotide comprising a nucleotide sequencewhich encodes a protein comprising the amino acid sequence of SEQ IDNO:49, comprising the steps of: (a) introducing into host cells one ormore vectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate ofsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 5. A method for identifying an agent which is an inhibitor of aprotein, said protein having fatty acid transport activity and beingencoded by a polynucleotide comprising a nucleotide sequence whichencodes a FATP2, wherein said polynucleotide hybridizes to a complementof a polynucleotide consisting of SEQ ID NO:48 under stringencyconditions of 6×SSC at 65° C., followed by two or more washes in0.2×SSC/0.5% SDS at 65° C., comprising the steps of: (a) introducinginto host cells one or more vectors comprising a polynucleotideexpressing said protein; (b) culturing a first aliquot of the host cellswith fatty acid substrate of said protein and with an agent being testedas an inhibitor of said protein; (c) culturing a second aliquot of thehost cells with fatty acid substrate of said protein; (d) measuring, inthe first and second aliquots, uptake of the fatty acid substrate of thehost cells; wherein less uptake of the fatty acid substrate in the firstaliquot compared to the second aliquot is indicative that the agent isan inhibitor of said protein.
 6. A method for identifying an agent whichis an inhibitor of a protein, said protein having fatty acid transportactivity and being encoded by a nucleic acid encoding a fatty acidtransport protein comprising an amino acid sequence having at least 95%amino acid sequence identify with the amino acid sequence in SEQ IDNO:49, comprising the steps of: (a) introducing into host cells one ormore vectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate ofsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 7. A method for identifying an agent which binds to a protein,said protein comprising the amino acid sequence of SEQ ID NO:49,comprising the steps of contacting the agent with the isolated proteinunder conditions appropriate for binding of the agent to the isolatedprotein, and detecting a resulting agent-protein complex.
 8. The methodof claim 7 wherein the step of contacting the agent with isolatedprotein is performed in an artificial membrane system.
 9. The method ofclaim 7 wherein the isolated protein is in isolated plasma membrane. 10.A method for identifying an agent which inhibits binding between anisolated protein and a ligand of said protein, wherein said proteincomprises the amino acid sequence of SEQ ID NO:49, comprising: (a)combining: (1) said isolated protein; (2) the ligand of said protein;and (3) a candidate agent to be assessed for its ability to inhibitbinding between said protein of (1) and the ligand of (2), underconditions appropriate for binding between the said protein of (1) andthe ligand of (2); (b) determining the extent to which said protein of(1) and the ligand of (2) bind; and (c) comparing the extent determinedin (b) with the extent to which binding of said protein of (1) and theligand of (2) occurs in the absence of the candidate agent to beassessed and under the same conditions appropriate for binding of saidprotein of (1) with the ligand of (2); wherein if the extent to whichbinding of said protein of (1) and the ligand of (2) occurs is less inthe presence of the candidate agent than in the absence of the candidateagent, the candidate agent is an agent which inhibits binding betweensaid protein and the ligand of said protein.
 11. The method of claim 10wherein (a) is performed in an artificial membrane system.
 12. Themethod of claim 10 wherein said isolated protein is in isolated plasmamembrane.
 13. A method for identifying an agent which binds to aprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP, wherein said polynucleotide hybridizes to a complement of thepolynucleotide of SEQ ID NO:48 under stringency conditions of 6×SSC at65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C.,comprising the steps of isolating the protein, contacting the agent withthe isolated protein under conditions appropriate for binding of theagent to the isolated protein, and detecting a resulting agent-proteincomplex.
 14. The method of claim 13 wherein the step of contacting theagent with the isolated protein is performed in an artificial membranesystem.
 15. The method of claim 13 wherein the isolated protein is inisolated plasma membrane.
 16. A method for identifying an agent whichinhibits binding between (1) an isolated protein, said protein havingfatty acid transport activity and encoded by a polynucleotide comprisinga nucleotide sequence which encodes a FATP, wherein said polynucleotidehybridizes to a complement of the polynucleotide of SEQ ID NO:48 understringency conditions of 6×SSC at 65° C., followed by two or more washesin 0.2×SSC/0.5% SDS at 65° C., and (2) a ligand of said protein,comprising: (a) combining: (1) said isolated protein; (2) the ligand ofsaid protein; and (3) a candidate agent to be assessed for its abilityto inhibit binding between said protein of (1) and the ligand of (2),under conditions appropriate for binding between said protein of (1) andthe ligand of (2); (b) determining the extent to which said protein of(1) and the ligand of (2) bind; and (c) comparing the extent determinedin (b) with the extent to which binding of said protein of (1) and theligand of (2) occurs in the absence of the candidate agent to beassessed and under the same conditions appropriate for binding of saidprotein of (1) with the ligand of (2); wherein if the extent to whichbinding of said protein of (1) and the ligand of (2) occurs is less inthe presence of the candidate agent than in the absence of the candidateagent, the candidate agent is an agent which inhibits binding betweensaid protein and the ligand of said protein.
 17. The method of claim 15wherein (a) is performed in an artificial membrane system.
 18. Themethod of claim 15 wherein the isolated protein is in isolated plasmamembrane.
 19. A method for identifying an agent which binds to a proteinhaving fatty acid transport activity and encoded by a nucleic acidencoding a fatty acid transport protein consisting of an amino acidsequence having at least 95% amino acid sequence identity with the aminoacid sequence of SEQ ID NO: 49, comprising the steps of isolating theprotein, contacting the agent with the isolated protein under conditionsappropriate for binding of the agent to the isolated protein, anddetecting a resulting agent-protein complex.
 20. The method of claim 19wherein the step of contacting the agent with isolated protein isperformed in an artificial membrane system.
 21. The method of claim 19wherein the isolated protein is in isolated plasma membrane.
 22. Amethod for identifying an agent which inhibits binding between anisolated protein having fatty acid transport activity and encoded by anucleic acid encoding a fatty acid transport protein comprising an aminoacid sequence, having at least 95% amino acid sequence identity with theamino acid sequence of SEQ ID NO: 49, and a ligand of said protein, saidmethod comprising: (a) combining: (1) said isolated protein; (2) theligand of said protein; and (3) a candidate agent to be assessed for itsability to inhibit binding between said protein of (1) and the ligand of(2), under conditions appropriate for binding between the said proteinof (1) and the ligand of (2); (b) determining the extent to which saidprotein of (1) and the ligand of (2) bind; and (c) comparing the extentdetermined in (b) with the extent to which binding of said protein of(1) and the ligand of (2) occurs in the absence of the candidate agentto be assessed and under the same conditions appropriate for binding ofsaid protein of (1) with the ligand of (2); wherein if the extent towhich binding of said protein of (1) and the ligand of (2) occurs isless in the presence of the candidate agent than in the absence of thecandidate agent, the candidate agent is an agent which inhibits bindingbetween said protein and the ligand of said protein.
 23. The method ofclaim 22 wherein (a) is performed in an artificial membrane system. 24.The method of claim 22 wherein said isolated protein is in isolatedplasma membrane.
 25. A method for identifying an agent which is aninhibitor of fatty acid uptake by a FATP, said FATP encoded by apolynucleotide comprising a nucleotide sequence which encodes a proteinconsisting of the amino acid sequence of SEQ ID NO:57, comprising thesteps of: a) maintaining test cells expressing said polynucleotide inthe presence of a fatty acid and an agent to be tested as an inhibitorof fatty acid uptake; b) measuring uptake of the fatty acid in the testcells; and c) comparing uptake of the fatty acid in the test cells withuptake of the fatty acid in suitable control cells; wherein lower uptakeof the fatty acid in the test cells compared to uptake of the fatty acidin the control cells is indicative that the agent is an inhibitor offatty acid uptake by said protein.
 26. A method for identifying an agentwhich is an inhibitor of fatty acid uptake by a protein, said proteinhaving fatty acid transport activity and encoded by a polynucleotidecomprising a nucleotide sequence which encodes a FATP6, wherein saidpolynucleotide hybridizes to a complement of a polynucleotide consistingof SEQ ID NO:56 under stringency conditions of 6×SSC at 65° C., followedby two or more washes in 0.2×SSC/0.5% SDS at 65° C., comprising thesteps of: a) maintaining test cells expressing said polynucleotide inthe presence of a fatty acid and an agent to be tested as an inhibitorof fatty acid uptake; b) measuring uptake of the fatty acid in the testcells; and c) comparing uptake of the fatty acid in the test cells withuptake of the fatty acid in suitable control cells; wherein lower uptakeof the fatty acid in the test cells compared to uptake of the fatty acidin the control cells is indicative that the agent is an inhibitor offatty acid uptake by said protein.
 27. A method for identifying an agentwhich is an inhibitor of fatty acid uptake by a protein, said proteinhaving fatty acid transport activity and being encoded by a nucleic acidencoding a fatty acid transport protein comprising an amino acidsequence having at least 95% amino acid sequence identify with the aminoacid sequence in SEQ ID NO:57, comprising the steps of: a) maintainingtest cells expressing said polynucleotide in the presence of a fattyacid and an agent to be tested as an inhibitor of fatty acid uptake; b)measuring uptake of the fatty acid in the test cells; and c) comparinguptake of the fatty acid in the test cells with uptake of the fatty acidin suitable control cells; wherein lower uptake of the fatty acid in thetest cells compared to uptake of the fatty acid in the control cells isindicative that the agent is an inhibitor of fatty acid uptake by saidprotein.
 28. A method for identifying an agent which is an inhibitor ofa protein, said protein encoded by a polynucleotide comprising anucleotide sequence which encodes a protein comprising the amino acidsequence in SEQ ID NO:57, comprising the steps of: (a) introducing intohost cells one or more vectors comprising a polynucleotide expressingsaid protein; (b) culturing a first aliquot of the host cells with fattyacid substrate of said protein and with an agent being tested as aninhibitor of said protein; (c) culturing a second aliquot of the hostcells with fatty acid substrate of said protein; (d) measuring, in thefirst and second aliquots, uptake of the fatty acid substrate of thehost cells; wherein less uptake of the fatty acid substrate in the firstaliquot compared to the second aliquot is indicative that the agent isan inhibitor of said protein.
 29. A method for identifying an agentwhich is an inhibitor of a protein, said protein being encoded by apolynucleotide comprising a nucleotide sequence which encodes a FATP6,wherein said polynucleotide hybridizes to a complement of apolynucleotide consisting of SEQ ID NO:56 under stringency conditions of6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at65° C., comprising the steps of: (a) introducing into host cells one ormore vectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate ofsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 30. A method for identifying an agent which is an inhibitor ofa protein, said protein having fatty acid transport activity and beingencoded by a nucleic acid encoding a fatty acid transport proteincomprising an amino acid sequence having at least 95% amino acidsequence identity with the amino acid sequence of SEQ ID NO:57,comprising the steps of: (a) introducing into host cells one or morevectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate orsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 31. A method for identifying an agent which is an inhibitor ofa fatty acid transport protein, comprising the steps of: (a) introducinginto cells one or more vectors comprising a gene encoding a cell surfaceprotein and a nucleic acid encoding the fatty acid transport protein;(b) contacting the host cells with anti-cell surface protein antibodyand labeled fatty acid substrate of the fatty acid transport protein;(c) contacting a first aliquot of the host cells with an agent beingtested as an inhibitor of the fatty acid transport protein, whileleaving a second aliquot of the host cells uncontacted with the agent;(d) identifying, in the first and second aliquots, the host cellsexpressing the cell surface protein by detecting the anti-cell surfaceprotein antibody bound to the host cells; and (e) measuring, in thefirst and second aliquots, uptake of the fatty acid substrate of thehost cells identified as expressing the cell surface protein; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of thefatty acid transport protein.
 32. The method of claim 31 wherein thehost cells regulatably express the FATP4 gene.
 33. The method of claim31 wherein the host cells are prokaryotes.
 34. The method of claim 31wherein the prokaryotes are E. coli.
 35. The method of claim 31 whereinthe fatty acid is a radioactively labeled fatty acid.
 36. A method foridentifying an agent which is an inhibitor of FATP4, comprising thesteps of: (a) introducing into cells one or more vectors comprising agene encoding a cell surface protein and a nucleic acid encoding FATP4;(b) contacting the host cells with anti-cell surface protein antibodyand labeled fatty acid substrate of FATP4; (c) contacting a firstaliquot of the host cells with an agent being tested as an inhibitor ofFATP4, while leaving a second aliquot of the host cells uncontacted withthe agent; (d) identifying, in the first and second aliquots, the hostcells expressing the cell surface protein by detecting the anti-cellsurface protein antibody bound to the host cells; and (e) measuring, inthe first and second aliquots, uptake of the fatty acid substrate of thehost cells identified as expressing the cell surface protein; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor ofFATP4.
 37. The method of claim 36 wherein the cell surface protein isCD2.
 38. The method of claim 36 wherein the fatty acid substrate isBODIPY-labeled.
 39. A method for identifying an agent which is aninhibitor of fatty acid uptake by a Fatty Acid Transport Protein (FATP),said FATP encoded by a polynucleotide comprising a nucleotide sequencewhich encodes a protein consisting of the amino acid sequence of SEQ IDNO:53, comprising the steps of: a) maintaining test cells expressingsaid polynucleotide in the presence of a fatty acid and an agent to betested as an inhibitor of fatty acid uptake; b) measuring uptake of thefatty acid in the test cells; and c) comparing uptake of the fatty acidin the test cells with uptake of the fatty acid in suitable controlcells; wherein lower uptake of the fatty acid in the test cells comparedto uptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 40. A methodfor identifying an agent which is an inhibitor of fatty acid uptake by aprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP2, wherein said polynucleotide hybridizes to a complement of apolynucleotide consisting of SEQ ID NO:52 under stringency conditions of6×SSC at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at65° C., comprising the steps of: a) maintaining test cells expressingsaid polynucleotide in the presence of a fatty acid and an agent to betested as an inhibitor of fatty acid uptake; b) measuring uptake of thefatty acid in the test cells; and c) comparing uptake of the fatty acidin the test cells with uptake of the fatty acid in suitable controlcells; wherein lower uptake of the fatty acid in the test cells comparedto uptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 41. A methodfor identifying an agent which is an inhibitor of fatty acid uptake by aprotein, said protein having fatty acid transport activity and beingencoded by a nucleic acid encoding a fatty acid transport proteincomprising an amino acid sequence having at least 95% amino acidsequence identity with the amino acid sequence of SEQ ID NO:53,comprising the steps of: a) maintaining test cells expressing saidpolynucleotide in the presence of a fatty acid and an agent to be testedas an inhibitor of fatty acid uptake; b) measuring uptake of the fattyacid in the test cells; and c) comparing uptake of the fatty acid in thetest cells with uptake of the fatty acid in suitable control cells;wherein lower uptake of the fatty acid in the test cells compared touptake of the fatty acid in the control cells is indicative that theagent is an inhibitor of fatty acid uptake by said protein.
 42. A methodfor identifying an agent which is an inhibitor of a protein, saidprotein encoded by a polynucleotide comprising a nucleotide sequencewhich encodes a protein comprising the amino acid sequence of SEQ IDNO:53, comprising the steps of: (a) introducing into host cells one ormore vectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate ofsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 43. A method for identifying an agent which is an inhibitor ofa protein, said protein having fatty acid transport activity and beingencoded by a polynucleotide comprising a nucleotide sequence whichencodes a FATP2, wherein said polynucleotide hybridizes to a complementof a polynucleotide consisting of SEQ ID NO:52 under stringencyconditions of 6×SSC at 65° C., followed by two or more washes in0.2×SSC/0.5% SDS at 65° C., comprising the steps of: (a) introducinginto host cells one or more vectors comprising a polynucleotideexpressing said protein; (b) culturing a first aliquot of the host cellswith fatty acid substrate of said protein and with an agent being testedas an inhibitor of said protein; (c) culturing a second aliquot of thehost cells with fatty acid substrate of said protein; (d) measuring, inthe first and second aliquots, uptake of the fatty acid substrate of thehost cells; wherein less uptake of the fatty acid substrate in the firstaliquot compared to the second aliquot is indicative that the agent isan inhibitor of said protein.
 44. A method for identifying an agentwhich is an inhibitor of a protein, said protein having fatty acidtransport activity and being encoded by a nucleic acid encoding a fattyacid transport protein comprising an amino acid sequence having at least95% amino acid sequence identify with the amino acid sequence in SEQ IDNO:53, comprising the steps or: (a) introducing into host cells one ormore vectors comprising a polynucleotide expressing said protein; (b)culturing a first aliquot of the host cells with fatty acid substrate ofsaid protein and with an agent being tested as an inhibitor of saidprotein; (c) culturing a second aliquot of the host cells with fattyacid substrate of said protein; (d) measuring, in the first and secondaliquots, uptake of the fatty acid substrate of the host cells; whereinless uptake of the fatty acid substrate in the first aliquot compared tothe second aliquot is indicative that the agent is an inhibitor of saidprotein.
 45. A method for identifying an agent which binds to a protein,said protein comprising the amino acid sequence of SEQ ID NO: 53,comprising the steps of contacting the agent with the isolated proteinunder conditions appropriate for binding or the agent to the isolatedprotein, and detecting a resulting agent-protein complex.
 46. The methodof claim 45 wherein the step of contacting the agent with isolatedprotein is performed in an artificial membrane system.
 47. The method ofclaim 45 wherein the isolated protein is in an isolated plasma membrane.48. A method for identifying an agent which binds to a protein, saidprotein comprising the amino acid sequence of SEQ ID NO: 57 comprisingthe steps of contacting the agent with the isolated protein underconditions appropriate for binding of the agent to the isolated protein,and detecting a resulting agent-protein complex.
 49. The method of claim48 wherein the step of contacting the agent with isolated protein isperformed in an artificial membrane system.
 50. The method of claim 48wherein the isolated protein is in an isolated plasma membrane.
 51. Amethod for identifying an agent which inhibits binding between anisolated protein and a ligand of said protein, wherein said proteincomprises the amino acid sequence of SEQ ID NO: 53, comprising: (a)combining: (1) said isolated protein; (2) the ligand of said protein;and (3) a candidate agent to be assessed for its ability to inhibitbinding between said protein of (1) and the ligand of (2), underconditions appropriate for binding between the said protein of (1) andthe ligand of (2); (b) determining the extent to which said protein of(1) and the ligand of (2) bind; and (c) comparing the extent determinedin (b) with the extent to which binding of said protein of (1) and theligand of (2) occurs in the absence of the candidate agent to beassessed and under the same conditions appropriate for binding of saidprotein of (1) with the ligand of (2); wherein if the extent to whichbinding of said protein of (1) and the ligand of (2) occurs is less inthe presence of the candidate agent than in the absence of the candidateagent, the candidate agent is an agent which inhibits binding betweensaid protein and the ligand of said protein.
 52. The method of claim 51wherein (a) is performed in an artificial membrane system.
 53. Themethod of claim 51 wherein said isolated protein is in an isolatedplasma membrane.
 54. A method for identifying an agent which inhibitsbinding between an isolated protein and a ligand of said protein,wherein said protein comprises the amino acid sequence of SEQ ID NO: 57,comprising: (a) combining: (1) said isolated protein; (2) the ligand ofsaid protein; and (3) a candidate agent to be assessed for its abilityto inhibit binding between said protein of (1) and the ligand of (2),under conditions appropriate for binding between the said protein of (1)and the ligand of (2); (b) determining the extent to which said proteinof (1) and the ligand of (2) bind; and (c) comparing the extentdetermined in (b) with the extent to which binding of said protein of(1) and the ligand of (2) occurs in the absence of the candidate agentto be assessed and under the same conditions appropriate for binding ofsaid protein of (1) with the ligand of (2); wherein if the extent towhich binding of said protein of(1) and the ligand of (2) occurs is lessin the presence of the candidate agent than in the absence of thecandidate agent, the candidate agent is an agent which inhibits bindingbetween said protein and the ligand of said protein.
 55. The method ofclaim 54 wherein (a) is performed in an artificial membrane system. 56.The method of claim 54 wherein said isolated protein is in an isolatedplasma membrane.
 57. A method for identifying an agent which binds to aprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP, wherein said polynucleotide hybridizes to a complement of thepolynucleotide of SEQ ID NO: 52 under stringency conditions of 6×SSC at65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C.,comprising the steps of isolating the protein, contacting the agent withthe isolated protein under conditions appropriate for binding of theagent to the isolated protein, and detecting a resulting agent-proteincomplex.
 58. The method of claim 57 wherein the step of contacting theagent with the isolated protein is performed in an artificial membranesystem.
 59. The method of claim 57 wherein the isolated protein is in anisolated plasma membrane.
 60. A method for identifying an agent whichbinds to a protein, said protein having fatty acid transport activityand encoded by a polynucleotide comprising a nucleotide sequence whichencodes a FATP, wherein said polynucleotide hybridizes to a complementof the polynucleotide of SEQ ID NO: 56 under stringency conditions of6×SSC, at 65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at65° C., comprising the steps of isolating the protein, contacting theagent with the isolated protein under conditions appropriate for bindingof the agent to the isolated protein, and detecting a resultingagent-protein complex.
 61. The method of claim 60 wherein the step ofcontacting the agent with the isolated protein is performed in anartificial membrane system.
 62. The method of claim 60 wherein theisolated protein is in an isolated plasma membrane.
 63. A method foridentifying an agent which inhibits binding between (1) an isolatedprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP, wherein said polynucleotide hybridizes to a complement of thepolynucleotide of SEQ ID NO: 52 under stringency conditions of 6×SSC at65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C.,and (2) a ligand of said protein, comprising: (a) combining: (1) saidisolated protein; (2) the ligand of said protein; and (3) a candidateagent to be assessed for its ability to inhibit binding between saidprotein of (1) and the ligand of (2), under conditions appropriate forbinding between said protein of (1) and the ligand of (2); (b)determining the extent to which said protein of (1) and the ligand of(2) bind; and (c) comparing the extent determined in (b) with the extentto which binding of said protein of (1) and the ligand of (2) occurs inthe absence of the candidate agent to be assessed and under the sameconditions appropriate for binding of said protein of (1) with theligand of (2); wherein if the extent to which binding of said protein of(1) and the ligand of (2) occurs is less in the presence of thecandidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits binding between said proteinand the ligand of said protein.
 64. The method of claim 63 wherein thestep of contacting the agent with the isolated protein is performed inan artificial membrane system.
 65. The method of claim 63 wherein theisolated protein is in isolated plasma membrane.
 66. A method foridentifying an agent which inhibits binding between (1) an isolatedprotein, said protein having fatty acid transport activity and encodedby a polynucleotide comprising a nucleotide sequence which encodes aFATP, wherein said polynucleotide hybridizes to a complement of thepolynucleotide of SEQ ID NO: 56 under stringency conditions of 6×XSC at65° C., followed by two or more washes in 0.2×SSC/0.5% SDS at 65° C.,and (2) a ligand of said protein, comprising: (a) combining: (1) saidisolated protein; (2) the ligand of said protein; and (3) a candidateagent to be assessed for its ability to inhibit binding between saidprotein of (1) and the ligand or(2), under conditions appropriate forbinding between said protein of (1) and the ligand of (2); (b)determining the extent to which said protein of (1) and the ligand of(2) bind; and (c) comparing the extent determined in (b) with the extentto which binding of said protein of (1) and the ligand of (2) occurs inthe absence of the candidate agent to be assessed and under the saneconditions appropriate for binding of said protein of (1) with theligand of (2); wherein if the extent to which binding of said protein of(1) and the ligand of (2) occurs is less in the presence of thecandidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits binding between said proteinand the ligand of said protein.
 67. The method of claim 66 wherein thestop of contacting the agent with the isolated protein is performed inan artificial membrane system.
 68. The method of claim 66 wherein theisolated protein is in isolated plasma membrane.
 69. A method foridentifying an agent which binds to a protein having fatty acidtransport activity and encoded by a nucleic acid encoding a fatty acidtransport protein consisting of an amino acid sequence having at least95% amino acid sequence identity with the amino acid sequence of SEQ IDNO: 53, comprising the steps of isolating the protein, contacting theagent with the isolated protein under conditions appropriate for bindingof the agent to the isolated protein, and detecting a resultingagent-protein complex.
 70. The method of claim 69 wherein the step ofcontacting the agent with isolated protein is performed in an artificialmembrane system.
 71. The method of claim 69 wherein the isolated proteinis in an isolated plasma membrane.
 72. A method for identifying an agentwhich binds to a protein having fatty acid transport activity andencoded by a nucleic acid encoding a fatty acid transport proteinconsisting of an amino acid sequence having at least 95% amino acidsequence identity with the amino acid sequence of SEQ ID NO: 57,comprising the steps of isolating the protein, contacting the agent withthe isolated protein under conditions appropriate for binding of theagent to the isolated protein, and detecting a resulting agent-proteincomplex.
 73. The method of claim 72 wherein the step of contacting theagent with isolated protein is performed in an artificial membranesystem.
 74. The method of claim 72 wherein the isolated protein is in anisolated plasma membrane.
 75. A method for identifying an agent whichinhibits binding between an isolated protein having fatty acid transportactivity and encoded by a nucleic acid encoding a fatty acid transportprotein comprising an amino acid sequence, having at least 95% aminoacid sequence identity with the amino acid sequence of SEQ ID NO: 53,and a ligand of said protein, said method comprising: (a) combining: (1)said isolated protein; (2) the ligand of said protein; and (3) acandidate agent to be assessed for its ability to inhibit bindingbetween said protein of (1) and the ligand of (2), under conditionsappropriate for binding between the said protein of (1) and the ligandof (2); (b) determining the extent to which said protein of (1) and theligand of (2) bind; and (c) comparing the extent determined in (b) withthe extent to which binding of said protein of (1) and the ligand of (2)occurs in the absence of the candidate agent to be assessed and underthe same conditions appropriate for binding of said protein of (1) withthe ligand of (2); wherein if the extent to which binding of saidprotein of (1) and the ligand of (2) occurs is less in the presence ofthe candidate agent than in the absence of the candidate agent, thecandidate agent is an agent which inhibits binding between said proteinand the ligand of said protein.
 76. The method of claim 75 wherein (a)is performed in an artificial membrane system.
 77. The method of claim75 wherein said isolated protein is in an isolated plasma membrane. 78.A method for identifying an agent which inhibits binding between anisolated protein having fatty acid transport activity and encoded by anucleic acid encoding a fatty acid transport protein comprising an aminoacid sequence, having at least 95% amino acid sequence identity with theamino acid sequence of SEQ ID NO: 57, and a ligand of said protein, saidmethod comprising: (a) combining: (1) said isolated protein; (2) theligand of said protein; and (3) a candidate agent to be assessed for itsability to inhibit binding between said protein of (1) and the ligand of(2), under conditions appropriate for binding between the said proteinof (1) and the ligand of (2); (b) determining the extent to which saidprotein of (1) and the ligand of (2) bind; and (c) comparing the extentdetermined in (b) with the extent to which binding of said protein of(1) and the ligand of (2) occurs in the absence of the candidate agentto be assessed and under the same conditions appropriate for binding ofsaid protein of (1) with the ligand of (2); wherein if the extent towhich binding of said protein of (1) and the ligand of (2) occurs isless in the presence of the candidate agent than in the absence of thecandidate agent, the candidate agent is an agent which inhibits bindingbetween said protein and the ligand of said protein.
 79. The method ofclaim 78 wherein (a) is performed in all artificial membrane system. 80.The method of claim 78 wherein said isolated protein is in an isolatedplasma membrane.